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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer</title><author><name sortKey="Costea, Teodora" sort="Costea, Teodora" uniqKey="Costea T" first="Teodora" last="Costea">Teodora Costea</name><affiliation><nlm:aff id="af1-ijms-21-00401">Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>teodora.costea@umfcd.ro</email></nlm:aff></affiliation></author><author><name sortKey="Vlad, Oana Cezara" sort="Vlad, Oana Cezara" uniqKey="Vlad O" first="Oana Cezara" last="Vlad">Oana Cezara Vlad</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author><author><name sortKey="Miclea, Luminita Claudia" sort="Miclea, Luminita Claudia" uniqKey="Miclea L" first="Luminita-Claudia" last="Miclea">Luminita-Claudia Miclea</name><affiliation><nlm:aff id="af3-ijms-21-00401">Department of Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>luminita.miclea@umfcd.ro</email></nlm:aff></affiliation><affiliation><nlm:aff id="af4-ijms-21-00401">Research Excellence Center in Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania</nlm:aff></affiliation></author><author><name sortKey="Ganea, Constanta" sort="Ganea, Constanta" uniqKey="Ganea C" first="Constanta" last="Ganea">Constanta Ganea</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author><author><name sortKey="Szoll Si, Janos" sort="Szoll Si, Janos" uniqKey="Szoll Si J" first="János" last="Szöll Si">János Szöll Si</name><affiliation><nlm:aff id="af5-ijms-21-00401">Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;<email>szollo@med.unideb.hu</email></nlm:aff></affiliation><affiliation><nlm:aff id="af6-ijms-21-00401">MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary</nlm:aff></affiliation></author><author><name sortKey="Mocanu, Maria Magdalena" sort="Mocanu, Maria Magdalena" uniqKey="Mocanu M" first="Maria-Magdalena" last="Mocanu">Maria-Magdalena Mocanu</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31936346</idno><idno type="pmc">7013436</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013436</idno><idno type="RBID">PMC:7013436</idno><idno type="doi">10.3390/ijms21020401</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000A28</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A28</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer</title><author><name sortKey="Costea, Teodora" sort="Costea, Teodora" uniqKey="Costea T" first="Teodora" last="Costea">Teodora Costea</name><affiliation><nlm:aff id="af1-ijms-21-00401">Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>teodora.costea@umfcd.ro</email></nlm:aff></affiliation></author><author><name sortKey="Vlad, Oana Cezara" sort="Vlad, Oana Cezara" uniqKey="Vlad O" first="Oana Cezara" last="Vlad">Oana Cezara Vlad</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author><author><name sortKey="Miclea, Luminita Claudia" sort="Miclea, Luminita Claudia" uniqKey="Miclea L" first="Luminita-Claudia" last="Miclea">Luminita-Claudia Miclea</name><affiliation><nlm:aff id="af3-ijms-21-00401">Department of Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>luminita.miclea@umfcd.ro</email></nlm:aff></affiliation><affiliation><nlm:aff id="af4-ijms-21-00401">Research Excellence Center in Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania</nlm:aff></affiliation></author><author><name sortKey="Ganea, Constanta" sort="Ganea, Constanta" uniqKey="Ganea C" first="Constanta" last="Ganea">Constanta Ganea</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author><author><name sortKey="Szoll Si, Janos" sort="Szoll Si, Janos" uniqKey="Szoll Si J" first="János" last="Szöll Si">János Szöll Si</name><affiliation><nlm:aff id="af5-ijms-21-00401">Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;<email>szollo@med.unideb.hu</email></nlm:aff></affiliation><affiliation><nlm:aff id="af6-ijms-21-00401">MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary</nlm:aff></affiliation></author><author><name sortKey="Mocanu, Maria Magdalena" sort="Mocanu, Maria Magdalena" uniqKey="Mocanu M" first="Maria-Magdalena" last="Mocanu">Maria-Magdalena Mocanu</name><affiliation><nlm:aff id="af2-ijms-21-00401">Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Tomasetti, C" uniqKey="Tomasetti C">C. Tomasetti</name></author><author><name sortKey="Li, L" uniqKey="Li L">L. Li</name></author><author><name sortKey="Vogelstein, B" uniqKey="Vogelstein B">B. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id><journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id><journal-id journal-id-type="publisher-id">ijms</journal-id><journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title></journal-title-group><issn pub-type="epub">1422-0067</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31936346</article-id><article-id pub-id-type="pmc">7013436</article-id><article-id pub-id-type="doi">10.3390/ijms21020401</article-id><article-id pub-id-type="publisher-id">ijms-21-00401</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3824-4222</contrib-id><name><surname>Costea</surname><given-names>Teodora</given-names></name><xref ref-type="aff" rid="af1-ijms-21-00401">1</xref></contrib><contrib contrib-type="author"><name><surname>Vlad</surname><given-names>Oana Cezara</given-names></name><xref ref-type="aff" rid="af2-ijms-21-00401">2</xref></contrib><contrib contrib-type="author"><name><surname>Miclea</surname><given-names>Luminita-Claudia</given-names></name><xref ref-type="aff" rid="af3-ijms-21-00401">3</xref><xref ref-type="aff" rid="af4-ijms-21-00401">4</xref></contrib><contrib contrib-type="author"><name><surname>Ganea</surname><given-names>Constanta</given-names></name><xref ref-type="aff" rid="af2-ijms-21-00401">2</xref></contrib><contrib contrib-type="author"><name><surname>Szöllősi</surname><given-names>János</given-names></name><xref ref-type="aff" rid="af5-ijms-21-00401">5</xref><xref ref-type="aff" rid="af6-ijms-21-00401">6</xref></contrib><contrib contrib-type="author"><name><surname>Mocanu</surname><given-names>Maria-Magdalena</given-names></name><xref ref-type="aff" rid="af2-ijms-21-00401">2</xref><xref rid="c1-ijms-21-00401" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-ijms-21-00401"><label>1</label>Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>teodora.costea@umfcd.ro</email></aff><aff id="af2-ijms-21-00401"><label>2</label>Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>vlad.oana18@gmail.com</email> (O.C.V.);<email>constanta.ganea@gmail.com</email> (C.G.)</aff><aff id="af3-ijms-21-00401"><label>3</label>Department of Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;<email>luminita.miclea@umfcd.ro</email></aff><aff id="af4-ijms-21-00401"><label>4</label>Research Excellence Center in Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania</aff><aff id="af5-ijms-21-00401"><label>5</label>Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;<email>szollo@med.unideb.hu</email></aff><aff id="af6-ijms-21-00401"><label>6</label>MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary</aff><author-notes><corresp id="c1-ijms-21-00401"><label>*</label>Correspondence: <email>magda.mocanu@umfcd.ro</email>; Tel.: +40-745-084-184</corresp></author-notes><pub-date pub-type="epub"><day>08</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>21</volume><issue>2</issue><elocation-id>401</elocation-id><history><date date-type="received"><day>02</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>03</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.</p></abstract><kwd-group><kwd>chemoresistance</kwd><kwd>malignancy</kwd><kwd>phenolic compounds</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-ijms-21-00401"><title>1. Introduction</title><p>Cancer is one of the leading cause of death worldwide. It is usually caused by genome instability and mutations, which may be inherited, induced by environmental factors or represent a consequence of DNA replication errors [<xref rid="B1-ijms-21-00401" ref-type="bibr">1</xref>]. The signature characteristics of cancer are represented by: a high rate cellular multiplication escaping growth inhibitors, cell migration inducing subsequent metastasis, stimulation of local new blood vessel formation (angiogenesis), the capacity to resist cell senescence and death signals leading to inflammation, and an almost unlimited self-replicating capacity [<xref rid="B2-ijms-21-00401" ref-type="bibr">2</xref>]. </p><p>The number of cancer cases is expected to increase rapidly as populations grow, age and adopt negative lifestyle behaviors (smoking, lack of physical activity, Western diet) that increase cancer risk [<xref rid="B3-ijms-21-00401" ref-type="bibr">3</xref>,<xref rid="B4-ijms-21-00401" ref-type="bibr">4</xref>]. Lung, breast, colorectal and prostate cancer are considered to be the most prevalent types of cancer among population [<xref rid="B3-ijms-21-00401" ref-type="bibr">3</xref>]. </p><p>For women, <italic>breast cancer</italic> is the most common diagnosed malignancy, followed by cervix or uterine cancer [<xref rid="B3-ijms-21-00401" ref-type="bibr">3</xref>]. In Europe, it is estimated that breast cancer affects more than one in 10 women and accounts for more than 28% of female cancers [<xref rid="B5-ijms-21-00401" ref-type="bibr">5</xref>]. Risk factors for breast cancer include unmodifiable factors and lifestyle factors. Among unmodifiable factors, age (above 40 years), family history of cancer in first-degree relatives, hormonal profile (late menopause, early menarche), dense breast tissue, race and genetics (mutation in breast cancer susceptibility genes—<italic>BCRA1</italic> and <italic>BCRA2</italic> genes, <italic>TP53</italic>, genetic polymorphisms in genes encoding enzymes involved in estrogen metabolism pathways COMT, CYP1A1, CYP1B1, estrogen receptors ERα/ERβ, CYP17A1 and CYP19A1) are of great importance. Lifestyle factors include nulliparity, use of birth control pills, induced abortion or obesity [<xref rid="B6-ijms-21-00401" ref-type="bibr">6</xref>,<xref rid="B7-ijms-21-00401" ref-type="bibr">7</xref>,<xref rid="B8-ijms-21-00401" ref-type="bibr">8</xref>,<xref rid="B9-ijms-21-00401" ref-type="bibr">9</xref>,<xref rid="B10-ijms-21-00401" ref-type="bibr">10</xref>]. Although breast cancer usually appears in pre- and post-menopausal women, recently new cases have occurred even in young women, below 35 years. This represents a serious concern, due to higher incidence of advanced stages at diagnosis and poorer five-year survival rate [<xref rid="B11-ijms-21-00401" ref-type="bibr">11</xref>] compared to older women. Breast cancer represents a heterogeneous disease and it is clinically divided into three basic subtypes: (I) based on the level of expression of estrogen and progesterone receptors, (II) based on the human epidermal growth factor 2 (HER2) and (III) a third subtype, when neither estrogen, progesterone or HER2 is expressed (triple negative breast cancer [<xref rid="B12-ijms-21-00401" ref-type="bibr">12</xref>]. Breast tumors expressing hormone receptors (mainly estrogen) are classified as luminal breast type (luminal A and B). Luminal A subtype has a better prognosis compared to luminal-B type, which is more aggressive, has a higher recurrence and an increased expression of growth receptor signaling molecules, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF), hepatocyte growth factor receptor (HGFR/MET) and Wnt/β-catenin [<xref rid="B13-ijms-21-00401" ref-type="bibr">13</xref>]. Increased growth receptor signaling genes is also observed for triple breast negative cancer [<xref rid="B14-ijms-21-00401" ref-type="bibr">14</xref>]. Nowadays, mammography represents the golden standard for breast cancer screening [<xref rid="B15-ijms-21-00401" ref-type="bibr">15</xref>]. </p><p><italic>Lung cancer</italic> is the most common cancer in men worldwide, and the fourth most frequent cancer in women [<xref rid="B16-ijms-21-00401" ref-type="bibr">16</xref>]. Lung cancer is often divided into four major types due to distinct clinic-pathological features: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which is further divided into squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma [<xref rid="B17-ijms-21-00401" ref-type="bibr">17</xref>]. Risk factors for lung cancer include smoking, environmental exposure to tobacco, radon, cooking oil vapors or hormonal factors (mainly in women). Moreover, genetic factors play a major role in lung cancer etiology [<xref rid="B18-ijms-21-00401" ref-type="bibr">18</xref>,<xref rid="B19-ijms-21-00401" ref-type="bibr">19</xref>,<xref rid="B20-ijms-21-00401" ref-type="bibr">20</xref>]. </p><p><italic>Colorectal cancer</italic> is one of the most preventable and treatable cancers if detected early; however, it has a multifactorial etiology. The hallmark of colorectal cancer is the presence of serrated or adenomatous polyps (adenoma) that usually occur in proximal or distal colon [<xref rid="B21-ijms-21-00401" ref-type="bibr">21</xref>]. Besides adenomas, patients with colorectal cancer have multiple aberrant crypt foci, which are microscopic mucosal abnormalities involved in early carcinogenesis [<xref rid="B22-ijms-21-00401" ref-type="bibr">22</xref>]. Main risk factors include alterations of gut microbiota [<xref rid="B23-ijms-21-00401" ref-type="bibr">23</xref>], Western diet [<xref rid="B24-ijms-21-00401" ref-type="bibr">24</xref>], obesity, hormonal status or chronic inflammatory bowel diseases [<xref rid="B25-ijms-21-00401" ref-type="bibr">25</xref>]. Genetic factors such as mutations in <italic>KRAS</italic>, <italic>BRAF</italic>, <italic>PI3K</italic> genes and polymorphisms in nucleic acid-binding protein 1, laminin γ 1, cyclin D2, T-box 3 are also involved in colorectal cancer etiology [<xref rid="B26-ijms-21-00401" ref-type="bibr">26</xref>,<xref rid="B27-ijms-21-00401" ref-type="bibr">27</xref>].</p><p><italic>Prostate cancer</italic> is the second most prevalent type of cancer among men, besides lung cancer. The majority of prostate cancers originate from luminal cells and do not have a neuroendocrine origin [<xref rid="B28-ijms-21-00401" ref-type="bibr">28</xref>]. Risk factors for prostate cancer include age, obesity, other diseases (diabetes), lifestyle behaviors (diet, lack of physical activity) and sexually transmitted diseases [<xref rid="B29-ijms-21-00401" ref-type="bibr">29</xref>]. Main characteristics of prostate cancer include activation of androgen receptor signaling, elevated lymphocyte infiltration and activation of inflammatory pathways [<xref rid="B30-ijms-21-00401" ref-type="bibr">30</xref>].</p><p>The above-mentioned cancer types have a common feature, which is represented by multidrug resistance (MDR) to chemotherapeutic treatments [<xref rid="B13-ijms-21-00401" ref-type="bibr">13</xref>,<xref rid="B28-ijms-21-00401" ref-type="bibr">28</xref>,<xref rid="B31-ijms-21-00401" ref-type="bibr">31</xref>]. Due to toxicity and lack of specificity of synthetic MDR agents, recent researches have focused on beneficial effects of natural compounds in overcoming MDR in cancer. According to recent research, polyphenols might overcome MDR through various mechanisms, which will be further discussed in our work [<xref rid="B32-ijms-21-00401" ref-type="bibr">32</xref>,<xref rid="B33-ijms-21-00401" ref-type="bibr">33</xref>,<xref rid="B34-ijms-21-00401" ref-type="bibr">34</xref>,<xref rid="B35-ijms-21-00401" ref-type="bibr">35</xref>].</p><p>Polyphenols are considered as important dietary components with biological activity due to a wide range of health benefits: antioxidant, anti-inflammatory, anti-carcinogenic, immunomodulatory, etc. [<xref rid="B36-ijms-21-00401" ref-type="bibr">36</xref>,<xref rid="B37-ijms-21-00401" ref-type="bibr">37</xref>]. Epidemiological studies have shown that intake of food rich in phenolic compounds have chemopreventive effects for cardiovascular, neurodegenerative diseases, cancer, obesity or diabetes [<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>]. Cancer chemopreventive effects of polyphenols are the consequence of antioxidant capacity, inhibition of proliferation, survival, angiogenesis and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens [<xref rid="B39-ijms-21-00401" ref-type="bibr">39</xref>]. </p><p>Polyphenols comprise a variety of compounds with a wide range of chemical structures, ranging from single molecules to high molecular weight polymers. Polyphenols have at least one aromatic ring and are classified as flavonoids and non-flavonoids in correlation with the number of aromatic ring [<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>,<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]. Flavonoids share a C<sub>6</sub>-C<sub>3</sub>-C<sub>6</sub> structural backbone and are further classified into flavones, flavonols, flavanones and flavan-3-ols [<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>]. Isoflavones, are also members of flavonoids family [<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>]. Non-flavonoid compounds include phenolcarboxylic acids (hydroxy-benzoic/hydroxy-cinnamic acids), ellagitannins, lignans, stilbenes and other phenolic compounds (curcumin, gingerol) [<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]. A selective list of polyphenols, which are frequently studied for overcoming MDR in breast, lung, prostate and colorectal cancer, is presented in <xref rid="ijms-21-00401-t001" ref-type="table">Table 1</xref>.</p></sec><sec id="sec2-ijms-21-00401"><title>2. Mechanism of Multidrug Resistance in Cancer</title><p>Earlier papers reported only few mechanisms responsible for MDR in cancer (<xref ref-type="fig" rid="ijms-21-00401-f001">Figure 1</xref>), such as (i) increased drug efflux through membrane pumps, (ii) detoxification mechanisms based on glutathione transferases activity, (iii) DNA damage repair that initially may be considered as an ally and further can turn into a resistant tool, and (iv) drug inactivation [<xref rid="B52-ijms-21-00401" ref-type="bibr">52</xref>]. However, recent papers described extended lists of mechanisms responsible for drug resistance in malignancy (<xref ref-type="fig" rid="ijms-21-00401-f001">Figure 1</xref>) such as modification of drug target, inhibition of cell death, involvement of cancer stem cells, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition, epigenetic variations, dysregulation of miRNAs and modulation of reactive oxygen species [<xref rid="B53-ijms-21-00401" ref-type="bibr">53</xref>,<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>,<xref rid="B55-ijms-21-00401" ref-type="bibr">55</xref>]. </p><sec id="sec2dot1-ijms-21-00401"><title>2.1. Increase of Drug Efflux</title><p>At the plasma membrane level, the large family of ATP-binding cassette (ABC) transporter proteins is responsible mainly for the drug efflux [<xref rid="B56-ijms-21-00401" ref-type="bibr">56</xref>]. ABC transporters consist of two transmembrane domains and two intracellular nucleotide-binding domains. It is the nucleotide binding domains that bind ATP and hydrolyze it to ADP providing the plasma membrane pump with energy required to export xenobiotic compounds [<xref rid="B57-ijms-21-00401" ref-type="bibr">57</xref>]. There are 49 known <italic>ABC</italic> genes organized in subfamilies, from A to G, respectively 12 <italic>ABCA</italic>, 11 <italic>ABCB</italic>, 13 <italic>ABCC</italic>, 4 <italic>ABCD</italic>, 1 <italic>ABCE</italic>, 3 <italic>ABCF</italic> and 5 <italic>ABCG</italic> [<xref rid="B58-ijms-21-00401" ref-type="bibr">58</xref>]. The most studied ABC transporters are multidrug-resistance protein 1 (MDR1)/permeability-glycoprotein (P-pg)/ABCB1, MDR-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP)/ABCG2 [<xref rid="B56-ijms-21-00401" ref-type="bibr">56</xref>,<xref rid="B59-ijms-21-00401" ref-type="bibr">59</xref>]. The majority of ABC transporters are localized in the liver, kidney, intestine, but they can have ubiquitous localization as well [<xref rid="B56-ijms-21-00401" ref-type="bibr">56</xref>,<xref rid="B59-ijms-21-00401" ref-type="bibr">59</xref>,<xref rid="B60-ijms-21-00401" ref-type="bibr">60</xref>]. </p><p>High levels of MDR1 are expressed in colorectal cancer [<xref rid="B61-ijms-21-00401" ref-type="bibr">61</xref>], hepatocarcinoma [<xref rid="B62-ijms-21-00401" ref-type="bibr">62</xref>], breast cancer [<xref rid="B63-ijms-21-00401" ref-type="bibr">63</xref>], lung cancer [<xref rid="B64-ijms-21-00401" ref-type="bibr">64</xref>] or prostate cancer [<xref rid="B65-ijms-21-00401" ref-type="bibr">65</xref>]. Overexpression of ABC transporters in cancer is mediated by (i) increased activity of proteins involved in the MAPK (HRas, ERK1/2, JNK), PI3K/AKT, mTOR, JNK, PKC signaling pathways, (ii) activation of EGF/FGF growth factors [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>,<xref rid="B66-ijms-21-00401" ref-type="bibr">66</xref>,<xref rid="B67-ijms-21-00401" ref-type="bibr">67</xref>,<xref rid="B68-ijms-21-00401" ref-type="bibr">68</xref>], (iii) nuclear localization of Y-box binding protein 1 (YB-1) in solid tumors [<xref rid="B69-ijms-21-00401" ref-type="bibr">69</xref>,<xref rid="B70-ijms-21-00401" ref-type="bibr">70</xref>], (iv) increased COX-2 activity [<xref rid="B71-ijms-21-00401" ref-type="bibr">71</xref>], (v) activation of VEGF2 (vascular endothelial growth factor receptor 2) by VEGF in tumor microenvironment [<xref rid="B70-ijms-21-00401" ref-type="bibr">70</xref>], (vi) activation of nuclear receptors PXR and CAR [<xref rid="B72-ijms-21-00401" ref-type="bibr">72</xref>,<xref rid="B73-ijms-21-00401" ref-type="bibr">73</xref>,<xref rid="B74-ijms-21-00401" ref-type="bibr">74</xref>] and (vii) hypoxia [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>]. According to recent studies inhibition of ERK1/2, NF-κB pathways and increased sensitivity to <italic>all</italic>-trans retinoic acid (a ligand of retinoic acid receptors RARs) render cancer cells more sensitive to chemotherapeutic agents, due to reduced P-gp mediated efflux activity [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>,<xref rid="B76-ijms-21-00401" ref-type="bibr">76</xref>,<xref rid="B77-ijms-21-00401" ref-type="bibr">77</xref>]. </p><p>Moreover, extensive studies have shown a strong correlation between ABC transporters activity and <italic>TP53</italic> tumor suppressor gene [<xref rid="B78-ijms-21-00401" ref-type="bibr">78</xref>,<xref rid="B79-ijms-21-00401" ref-type="bibr">79</xref>]. It is well known that <italic>TP53</italic> mutations occur in almost 50% of cancers and are involved in inhibition of apoptosis [<xref rid="B80-ijms-21-00401" ref-type="bibr">80</xref>]. According to Sullivan G. and his co-workers <italic>TP53</italic> mutations become increasingly frequent as prostate cancer advances in stage and this is strongly correlated with increased MRP1 expression [<xref rid="B79-ijms-21-00401" ref-type="bibr">79</xref>]. </p><p>Several chemotherapeutic agents (doxorubicin, daunorubicin, vincristine, vinblastine, actinomycin D, paclitaxel, docetaxel, etoposide) and molecular targeted anticancer compounds (i.e., tyrosine kinase inhibitors, such as imatinib, erlotinib, sunitinib) are substrates for MDR1 [<xref rid="B81-ijms-21-00401" ref-type="bibr">81</xref>,<xref rid="B82-ijms-21-00401" ref-type="bibr">82</xref>,<xref rid="B83-ijms-21-00401" ref-type="bibr">83</xref>,<xref rid="B84-ijms-21-00401" ref-type="bibr">84</xref>] and this fact has negative impact on drug efflux in malignant cells. In this context, many attempts have been reported to overcome MDR. </p><p>Two main strategies have been employed to prevent drug resistance mediated by ABC protein transporters, namely (i) co-administration of MDR1 inhibitors with chemotherapeutical drugs with the aim to increase intracellular accumulation of drug and (ii) substrate competition by co-administration of MDR1 substrate together with the anticancer drug [<xref rid="B85-ijms-21-00401" ref-type="bibr">85</xref>]. Some of the first modulators of MDR1 identified are calcium influx blockers (i.e., verapamil, nicardipine nifedipine), which increased the cytotoxicity of anticancer drugs in cancer cell lines [<xref rid="B86-ijms-21-00401" ref-type="bibr">86</xref>,<xref rid="B87-ijms-21-00401" ref-type="bibr">87</xref>,<xref rid="B88-ijms-21-00401" ref-type="bibr">88</xref>]. Regrettably, the results from preclinical studies were difficult to apply in clinical trials for several reasons (i) necessity of higher concentrations, which in turn induced systemic toxicity, (ii) low selectivity and specificity due to the expression of the target in different tissues or (iii) low efficiency due to functional redundancy of ABC protein transporter family [<xref rid="B85-ijms-21-00401" ref-type="bibr">85</xref>]. Recently, PPAR δ ligands (rosiglitazone and pioglitazone) were found to inhibit drug resistance in breast cancer cells by internalization of ABCG2 to cytoplasm [<xref rid="B89-ijms-21-00401" ref-type="bibr">89</xref>]. Further research studies are needed to understand the molecular mechanism and to identify the optimal doses of MDR1 inhibitors for the development of new inhibitors of ABC protein transporters. </p></sec><sec id="sec2dot2-ijms-21-00401"><title>2.2. Detoxification Mechanisms and Inactivation of Anticancer Drugs</title><p>Downregulation or mutations in the proteins or enzymes involved in activation of chemotherapeutic agents can be responsible for drug resistance [<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>]. For example, in tumor cells resistant to capecitabine, the gene responsible for the synthesis of thymidine phosphorylase, an enzyme responsible for generation of the nucleotides, can be inactivated by hypermethylation [<xref rid="B91-ijms-21-00401" ref-type="bibr">91</xref>]. Carbonyl reduction of doxorubicin induced by aldo-keto reductase is responsible for transformation of doxorubicin into doxorubicinol, which is an inactive form. Administration of both chemotherapeutic drugs and inhibitors of aldo-keto reductase is recommended to overcome inactivation of doxorubicin and to increase its therapeutic activity [<xref rid="B92-ijms-21-00401" ref-type="bibr">92</xref>]. </p><p>Other important pathways of drug inactivation involve the CYP450 system (mainly CYP2B6, CYP2C9, CYP2C19, CYP2D6), glutathione-S-transferase (GST) superfamily or uridine diphospho-glucuronosyltransferase (UGT) superfamily [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>]. For example, CYP2D6 polymorphism is involved in tamoxifen variability among patients with breast cancer, since CYP2D6 is involved in tamoxifen metabolization to 4-hydroxytamoxifen and endoxifen, both of which display higher anti-estrogenic activity [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. Some of the first reports, reconfirmed later on, indicated that resistance to platinum could occur through drug inactivation by thiol glutathione, which activates the detoxification system (GST) [<xref rid="B94-ijms-21-00401" ref-type="bibr">94</xref>,<xref rid="B95-ijms-21-00401" ref-type="bibr">95</xref>]. It was reported that resistance to other chemotherapeutic agents (doxorubicin, tamoxifen, epirubicin), commonly used to treat breast cancer, is mediated by the polymorphisms in UGT superfamily [<xref rid="B96-ijms-21-00401" ref-type="bibr">96</xref>].</p></sec><sec id="sec2dot3-ijms-21-00401"><title>2.3. DNA Damage Repair</title><p>Several chemotherapeutic drugs interfere with DNA synthesis with the aim to induce senescence, apoptosis or cell cycle arrest in cancer cells [<xref rid="B97-ijms-21-00401" ref-type="bibr">97</xref>]. DNA-damaging compounds with anticancer properties can act through different mechanisms such as inducing DNA crosslinking (i.e., cisplatin, carboplatin, oxaliplatin), preventing DNA synthesis (i.e., antimetabolites that inhibit the activity of dihydropholate reductase) or inhibiting topoisomerase activity (i.e., doxorubicin, daunorubicin) [<xref rid="B98-ijms-21-00401" ref-type="bibr">98</xref>]. Nevertheless, these compounds do not have a specific tumor target and the selectivity of anticancer drugs is based on the rate of cell cycling. Tumor cells have a rapid cycling compared to normal cells and DNA damage response proteins (DDR) do not have enough time to repair DNA lesions [<xref rid="B99-ijms-21-00401" ref-type="bibr">99</xref>]. The major mechanisms of DNA repair pathways in response to chemotherapy are elegantly and thoroughly explained elsewhere [<xref rid="B99-ijms-21-00401" ref-type="bibr">99</xref>]. Briefly, these processes include (i) mismatch repair (MMR) mechanisms which remove mis-incorporated nucleotides during DNA replication [<xref rid="B100-ijms-21-00401" ref-type="bibr">100</xref>]; (ii) nucleotide excision repair (NER) which removes bulky DNA lesions, such as DNA adducts [<xref rid="B101-ijms-21-00401" ref-type="bibr">101</xref>]; (iii) base excision repair (BER) that corrects small base lesions which occur after DNA damage produced by oxidation, deamination or alkylation [<xref rid="B102-ijms-21-00401" ref-type="bibr">102</xref>]; (iv) homologous recombination (HR) which repairs DNA double-stranded breaks and inter-strand crosslinks [<xref rid="B103-ijms-21-00401" ref-type="bibr">103</xref>]; (v) non-homologous end-joining (NHEJ) with the aim to repair double-stranded breaks [<xref rid="B104-ijms-21-00401" ref-type="bibr">104</xref>]. </p><p>Recent reports demonstrate that MDR to platinum drugs in cancer cell lines, implicates multiple DDR pathways including HR, transcription-coupled NER and BER [<xref rid="B105-ijms-21-00401" ref-type="bibr">105</xref>]. MutL homolog 1 (MLH1) and MutL homolog 2 (MLH2)—proteins belonging to MMR system—have been evaluated by immunohistochemistry from patients with colorectal cancer and 10% of these patients presented MMR deficiency. Administration of 5-fluorouracil induced the improvement of survival only in patients without MMR deficiency, demonstrating the association between dysregulation in MMR processes and multidrug resistance [<xref rid="B106-ijms-21-00401" ref-type="bibr">106</xref>]. Due to constantly improving technology, the researchers might carry out genomic screening with the aim to identify potential DNA therapeutic targets responsible for MDR in malignancies. </p></sec><sec id="sec2dot4-ijms-21-00401"><title>2.4. Modification of Drug Target</title><p>A drug’s efficacy strongly depends on its molecular target. Alteration of these targets by means of different mechanisms (i.e., mutations) may lead to drug resistance [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>]. One of the most studied mechanisms of drug resistance in respect with modification of the drug target is focused on epidermal growth factor receptor (EGFR) [<xref rid="B107-ijms-21-00401" ref-type="bibr">107</xref>]. In non-small-cell lung cancer (NSCLC) activation mutations of EGFR in the tyrosine kinase domain had been identified. Small molecule inhibitors such as gefitinib and erlotinib are known to neutralize these modifications [<xref rid="B107-ijms-21-00401" ref-type="bibr">107</xref>]. Nevertheless, after two years of gefitinib treatment the disease can relapse, due to occurrence of secondary mutation (T790M) in EGFR [<xref rid="B108-ijms-21-00401" ref-type="bibr">108</xref>]. Second generation of EGFR tyrosine inhibitors (i.e., ponatinib) had been created to act against EGFR(T790M), but increased toxicity caused withdrawal of the drug from the market [<xref rid="B109-ijms-21-00401" ref-type="bibr">109</xref>]. Due to ability of cancer cells to survive by occurrence of additional mutations, new generations of tyrosine kinase inhibitors (TKI) against EGFR or other molecular targets are needed to be developed to overcome MDR and side effects associated with anticancer therapy. </p></sec><sec id="sec2dot5-ijms-21-00401"><title>2.5. Inhibition of Cell Death</title><p>Cancer cells escape cell death using several mechanisms such as dysregulation of apoptosis, inhibition of other non-apoptotic processes (i.e., autophagy, etc.) or stimulation of alternative survival pathways [<xref rid="B53-ijms-21-00401" ref-type="bibr">53</xref>]. The most studied mechanisms, which allow cancer cells to evade cell death and to acquire MDR, are the disturbance of apoptosis and inhibition of autophagy. The main proteins involved in apoptosis are the caspases, which can be activated by both intrinsic (in the mitochondria) and extrinsic (through tumor necrosis family factors that bind to cell death receptors) pathways [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>,<xref rid="B110-ijms-21-00401" ref-type="bibr">110</xref>,<xref rid="B111-ijms-21-00401" ref-type="bibr">111</xref>,<xref rid="B112-ijms-21-00401" ref-type="bibr">112</xref>]. </p><p>Mechanisms of drug resistance due to apoptosis deregulation include: (i) imbalance of Bcl-2 family members (downregulation of pro-apoptotic proteins Bax and upregulation of anti-apoptotic proteins BCL-X<sub>L</sub>, BCL-2), (ii) altered apoptotic regulators (downregulation of caspase−3, −8, −9 and upregulation of inhibitors of apoptosis proteins such as XIAP, FLIP, survivin), (iii) upregulation of ubiquitin binding proteins (sharpin), which regulates Bcl-2 and survivin [<xref rid="B113-ijms-21-00401" ref-type="bibr">113</xref>], (iv) decreased activity of p53 and PTEN [<xref rid="B80-ijms-21-00401" ref-type="bibr">80</xref>,<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>,<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>], (v) decreased activity of cytochrome C and Smac/DIABLO (which are responsible for caspases activation) [<xref rid="B114-ijms-21-00401" ref-type="bibr">114</xref>,<xref rid="B115-ijms-21-00401" ref-type="bibr">115</xref>], (vi) deregulated activity of cyclin-dependent kinases (CDK), protein tyrosine kinases (Her2,/neu, Her3, Her4) [<xref rid="B116-ijms-21-00401" ref-type="bibr">116</xref>] or different signaling pathways (GSK-3; STAT3, PI3K/AKT, mTOR) [<xref rid="B115-ijms-21-00401" ref-type="bibr">115</xref>,<xref rid="B117-ijms-21-00401" ref-type="bibr">117</xref>,<xref rid="B118-ijms-21-00401" ref-type="bibr">118</xref>] or (vii) amplification of gene expression of <italic>CYCLINS</italic> (<italic>A1, D1</italic>) [<xref rid="B119-ijms-21-00401" ref-type="bibr">119</xref>]. Checkpoint kinases (Chk1, Chk2), which are modulated by serine/threonine protein kinases (ATR), also play a major role in apoptosis since they promote activation of p21 and p53, which induce cell cycle arrest [<xref rid="B120-ijms-21-00401" ref-type="bibr">120</xref>].</p><p>Autophagy is involved in MDR through increased activity of AMP-protein kinase (AMPK), beclin-1 and activation of autophagy lysosomes systems (ALP) [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>,<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. ALP in most tumors may enhance the MDR phenotype through a protein clearance mechanism [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>]. Elevated autophagy lysosomes systems are involved in EGFR inhibitors (gefitinib, erlotinib), mTOR inhibitors (temsirolimus) or targeted therapy (imatinib) chemoresistance [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>].</p><p>It is reasonable to assume that genes, mRNA and proteins involved in disturbed apoptotic and autophagy processes are considered optimal targets to overcome multidrug resistance in malignant tumors. Against anti-apoptotic BCL-2 proteins both antisense oligonucleotides (i.e., oblimersen sodium) that target BCL-2 mRNA and small molecules which can interact with BH3 domains have been developed [<xref rid="B121-ijms-21-00401" ref-type="bibr">121</xref>,<xref rid="B122-ijms-21-00401" ref-type="bibr">122</xref>]. The last category might be divided in small molecules with BH3 mimetic activity (i.e., ABT-737, navitoclax/ABT-263/oral version of ABT-737) and small molecules with BH3 putative mimetic action (i.e., gossypol, obatoclax/a pan-BCL-2 inhibitor, etc.) [<xref rid="B123-ijms-21-00401" ref-type="bibr">123</xref>]. </p><p>Nevertheless, several mechanisms of drug resistance developed by cancer cells hindered the successful application of anti-apoptotic drugs in patients. For instance, clinical studies on combinatorial administration of several chemotherapeutics (i.e., dacarbazine, fludarabine, cyclophosphamide) and oblimersen did not bring favorable results in patients [<xref rid="B122-ijms-21-00401" ref-type="bibr">122</xref>,<xref rid="B124-ijms-21-00401" ref-type="bibr">124</xref>]. Polymorphism of BCL-2-like protein 11 (BIM) with different splicing variants resulted in lack of BH3 domain and resistance to targeted therapy in NSCLC positive for EGFR [<xref rid="B125-ijms-21-00401" ref-type="bibr">125</xref>]. </p><p>Stimulation of pro-apoptotic death receptors (i.e., DR4, DR5) localized in plasma membrane demonstrated in vitro and in vivo anti-proliferative activity, but clinical results have been unsatisfactory [<xref rid="B126-ijms-21-00401" ref-type="bibr">126</xref>,<xref rid="B127-ijms-21-00401" ref-type="bibr">127</xref>]. Nevertheless, preclinical experiments with the aim to test synergism of combinatorial administration of death receptors agonists and other anti-cancer drugs are under evaluation [<xref rid="B128-ijms-21-00401" ref-type="bibr">128</xref>,<xref rid="B129-ijms-21-00401" ref-type="bibr">129</xref>]. Recently, inhibitors of CDK (roscovitine, terameprocol, flavopiridol) are under investigation in different MDR cancers [<xref rid="B116-ijms-21-00401" ref-type="bibr">116</xref>]. </p><p>Moreover, it was shown that PPAR δ agonists (rosiglitazone) sensitizes colorectal cancer cells to 5-FU by downregulation of Bcl-2 proteins and upregulation of Bax [<xref rid="B130-ijms-21-00401" ref-type="bibr">130</xref>]. Inhibition of ALP using chloroquine and hydroxychloroquine is also under investigation in both preclinical and clinical studies [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>]. </p><p>Further preclinical experiments and successful clinical trials are needed to better understand the molecular mechanisms of anti-apoptotic/autophagy processes and to circumvent the drug resistance in cancer cells.</p></sec><sec id="sec2dot6-ijms-21-00401"><title>2.6. Cancer Stem Cells</title><p>There is increasing evidence that cancer stem cells (CSCs), a subpopulation of cells within the heterogenous tumor niche, are responsible for initiation of some primary tumors as well as metastasis and MDR [<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>,<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. CSCs are resistant to chemotherapy and radiotherapy given to their particular characteristics such as increased DNA damage repair, resistance to cell death mechanisms, evasion from immune response, adaptation to hypoxia and overexpression of MDR efflux pumps [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>,<xref rid="B131-ijms-21-00401" ref-type="bibr">131</xref>]. Several lines of action have been developed to overcome drug resistance in cancer stem cells. These include (i) new inhibitors against ABC transporters, (ii) antibodies conjugated with toxins or radioisotopes against ABC transporters, (iii) inhibitors of signaling pathways identified in cancer stem cells (i.e., Hedgehog signaling pathway) or (iv) activation of immune system against cancer stem cells [<xref rid="B131-ijms-21-00401" ref-type="bibr">131</xref>,<xref rid="B132-ijms-21-00401" ref-type="bibr">132</xref>]. In spite of the extensive efforts to address drug resistance in cancer stem cells there are still open questions needing to be answered. For instance, how is it possible that ABC transporters or Hedgehog signaling pathways can be targeted only in cancer stem cells and not in normal stem cells? In addition, recent papers underline the contribution of cancer niche as a crucial factor in drug resistance of CSCs [<xref rid="B133-ijms-21-00401" ref-type="bibr">133</xref>,<xref rid="B134-ijms-21-00401" ref-type="bibr">134</xref>]. Cancer associated fibroblasts stimulated 5-fluorouracil resistance in colon CSC by activating Wnt signaling [<xref rid="B135-ijms-21-00401" ref-type="bibr">135</xref>] or autocrine generation of inflammatory factors, such as interleukin-6 induced trastuzumab resistance in HER2 positive breast CSC [<xref rid="B136-ijms-21-00401" ref-type="bibr">136</xref>]. Besides addressing ABC transporters as therapeutic targets, CSC niche could represent a potential objective in further anticancer approaches with the aim to overcome MDR. </p></sec><sec id="sec2dot7-ijms-21-00401"><title>2.7. Tumor Heterogeneity</title><p>Genetic instability allows survival of the best adaptable clonal populations of malignant cells, and this heterogeneity represents one of the reasons for the failure of anticancer therapy [<xref rid="B137-ijms-21-00401" ref-type="bibr">137</xref>,<xref rid="B138-ijms-21-00401" ref-type="bibr">138</xref>]. It is already recognized that tumor heterogeneity implies two distinct types of processes, (i) tumor inter-heterogeneity, with tumors affecting the same organ, but with different characteristics in each patient, and (ii) tumor intra-heterogeneity, with two branches, spatial and temporal heterogeneity [<xref rid="B139-ijms-21-00401" ref-type="bibr">139</xref>]. Spatial heterogeneity is present in the same patient and it is characterized by different genotypes and phenotypes of the malignant clones in the primary and metastatic sites, while temporal heterogeneity expresses the changes which are taking place in the same tumor over the time [<xref rid="B139-ijms-21-00401" ref-type="bibr">139</xref>]. In cancer cells overexpressing hepatocyte growth factor receptor (HGFR/MET), heterogeneity occurred as a molecular mechanism of drug resistance after chemotherapy [<xref rid="B140-ijms-21-00401" ref-type="bibr">140</xref>]. Thus, after two years of targeted therapy against MET, two additional changes have been identified, <italic>KRAS</italic> mutation and co-amplification of <italic>HER2</italic> and/or <italic>EGFR</italic> genes [<xref rid="B140-ijms-21-00401" ref-type="bibr">140</xref>]. Chronical administration of the chemotherapeutic drugs demonstrated that in one or two years the diseases relapsed due to the ability of cancer cells to generate new clones and to find alternative pathways to survive and proliferate [<xref rid="B108-ijms-21-00401" ref-type="bibr">108</xref>,<xref rid="B141-ijms-21-00401" ref-type="bibr">141</xref>]. </p><p>In vitro and in vivo experiments have been performed to identify the culprit molecules or alternative pathways that confer drug resistance [<xref rid="B142-ijms-21-00401" ref-type="bibr">142</xref>,<xref rid="B143-ijms-21-00401" ref-type="bibr">143</xref>]. Escape of human epidermal growth factor receptor type 2 (HER2) from the inhibition with tyrosine kinase inhibitor (TKI) through alternative HER3 activation has been demonstrated in mammary cancer cell lines [<xref rid="B142-ijms-21-00401" ref-type="bibr">142</xref>]. Not only in case of chemotherapy, but also in case of hormone therapy the existence of adaptive mechanisms and acquired resistance has been reported [<xref rid="B144-ijms-21-00401" ref-type="bibr">144</xref>,<xref rid="B145-ijms-21-00401" ref-type="bibr">145</xref>]. Increased survival and reduction of prostate serum antigen (PSA) levels are described after androgen deprivation by enzalutamide in prostate cancers [<xref rid="B146-ijms-21-00401" ref-type="bibr">146</xref>]. However, secondary mutations are identified in castration-resistant prostate cancers after administration of enzalutamide [<xref rid="B147-ijms-21-00401" ref-type="bibr">147</xref>]. Similar to hormone therapy against prostate cancer, first results about administration of tamoxifen in estrogen receptor (ER) positive breast cancer patients have been promising and there are recommendations to increase the administration from five to 10 years [<xref rid="B148-ijms-21-00401" ref-type="bibr">148</xref>]. Notably, chronical administration of hormone therapy can cause resistance and most frequently alternative signaling pathways activated in estrogen resistant breast cancer are plasma membrane tyrosine kinase receptors, such as EGFR, HER2, IGF-1R or downstream kinases, such as ERK1/2, PI3K/AKT [<xref rid="B144-ijms-21-00401" ref-type="bibr">144</xref>,<xref rid="B149-ijms-21-00401" ref-type="bibr">149</xref>].</p><p>Increased exposure of the malignant cells to different anticancer agents amplifies the heterogeneity of the tumor and several overcoming therapies against drug resistance are proposed [<xref rid="B139-ijms-21-00401" ref-type="bibr">139</xref>]. These include (i) combination therapy against single target (i.e., TKI afatinib against EGFR and monoclonal antibody cetuximab against EGFR) [<xref rid="B150-ijms-21-00401" ref-type="bibr">150</xref>] or against multiple targets (i.e., a third generation TKI of EGFR(T790M) and navitoclax an inhibitor of ABC transporters) [<xref rid="B151-ijms-21-00401" ref-type="bibr">151</xref>]; (ii) sequential therapy to reduce the toxicity induced by combination of chemotherapeutic agents [<xref rid="B152-ijms-21-00401" ref-type="bibr">152</xref>] or (iii) targeted therapy after identification of genetic markers (i.e., patients with EGFR(T790M) mutation which can benefit from osimertinib treatment compared to patients with activating mutations in EGFR who can benefit by gefinitib/erolotinib/afatinib administration) [<xref rid="B153-ijms-21-00401" ref-type="bibr">153</xref>]. New experimental studies and different therapeutic approaches are required to find the optimal way to interfere with development of tumor malignancy. </p></sec><sec id="sec2dot8-ijms-21-00401"><title>2.8. Tumor Microenvironment (TME)</title><p>In spite of the fact that TME is formed from non-malignant structures (i.e., cancer associated fibroblast, immune cells, adipocytes, extracellular matrix molecules, blood and lymphatic vessels, and mesenchymal cells), in most cases they are considered as tumor-promoting factors [<xref rid="B154-ijms-21-00401" ref-type="bibr">154</xref>]. Main mechanisms involved in TME role in MDR are (i) abnormal tumor vasculature (promotion of angiogenesis and overexpression of VEGF), (ii) hypoxia, (iii) decreased pH (due to glycolysis), (iv) alterations in the expression of tumor suppressors and oncogenes [<xref rid="B155-ijms-21-00401" ref-type="bibr">155</xref>,<xref rid="B156-ijms-21-00401" ref-type="bibr">156</xref>,<xref rid="B157-ijms-21-00401" ref-type="bibr">157</xref>,<xref rid="B158-ijms-21-00401" ref-type="bibr">158</xref>] and (v) modulation of different signaling pathways (mTOR, ERK1/2) and growth-factors (FGF) [<xref rid="B159-ijms-21-00401" ref-type="bibr">159</xref>]. Among TME factors, hypoxia plays a major role in lung, colorectal, breast and prostate cancers MDR [<xref rid="B155-ijms-21-00401" ref-type="bibr">155</xref>,<xref rid="B160-ijms-21-00401" ref-type="bibr">160</xref>,<xref rid="B161-ijms-21-00401" ref-type="bibr">161</xref>,<xref rid="B162-ijms-21-00401" ref-type="bibr">162</xref>,<xref rid="B163-ijms-21-00401" ref-type="bibr">163</xref>]. Hypoxia induces HIF-1 (hypoxia-inducible factor 1) in tumor cells, upregulates the release of pro-angiogenic factors, increases the expression of growth-factor receptors (CXCR4) and MDR proteins (P-gp) [<xref rid="B164-ijms-21-00401" ref-type="bibr">164</xref>]. Moreover, the relatively low pH values—a direct consequence of hypoxia—are responsible for reduced cellular uptake of chemotherapeutic agents [<xref rid="B165-ijms-21-00401" ref-type="bibr">165</xref>].</p><p>Other important factors of TME which promote MDR are the overexpression of fatty acid synthase (FASN) and fatty acid-binding proteins (FBAP4, FBAP5, FBAP9) in breast/prostate tumor cells [<xref rid="B166-ijms-21-00401" ref-type="bibr">166</xref>,<xref rid="B167-ijms-21-00401" ref-type="bibr">167</xref>]. FSAN is required for de novo synthesis of fatty acids and is correlated with poor prognosis of cancer [<xref rid="B166-ijms-21-00401" ref-type="bibr">166</xref>]. Overexpression of FASN may induce drug resistance by (i) altering the membrane composition, thus decreasing the influx of chemotherapeutic agents; (ii) upregulation of HER2 or (iii) inhibition of apoptosis [<xref rid="B168-ijms-21-00401" ref-type="bibr">168</xref>,<xref rid="B169-ijms-21-00401" ref-type="bibr">169</xref>]. </p><p>According to recent research, the cellular components of the tumor stroma (fibroblasts, infiltrated immune cells or mesenchymal stromal cells) induce MDR through increased expression of cytokines (IL-6, IL-8, IL-18, IL-17), overexpression of HER2 and loss of PTEN (tumor suppressor gene) activity [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>,<xref rid="B170-ijms-21-00401" ref-type="bibr">170</xref>,<xref rid="B171-ijms-21-00401" ref-type="bibr">171</xref>,<xref rid="B172-ijms-21-00401" ref-type="bibr">172</xref>]. To date several small molecule inhibitors and antibodies against tumor stroma are in clinical trials (prinomastat, saridegib, bevacizumab, etc.) [<xref rid="B171-ijms-21-00401" ref-type="bibr">171</xref>].</p></sec><sec id="sec2dot9-ijms-21-00401"><title>2.9. Epithelial to Mesenchymal Transition (EMT)</title><p>Tumor microenvironment plays a major role in cancer cells ability to develop further features such as cell transition from epithelial to mesenchymal phenotype. This transformation gives them the advantage to migrate to secondary sites [<xref rid="B173-ijms-21-00401" ref-type="bibr">173</xref>]. EMT is considered to be an important mechanism by which tumors become metastatic and multidrug-resistant [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>,<xref rid="B174-ijms-21-00401" ref-type="bibr">174</xref>]. Drug resistance developed after administration of EGFR-target therapy (i.e., erlotinib and cetuximab) has been reported to be connected with EMT features [<xref rid="B175-ijms-21-00401" ref-type="bibr">175</xref>].</p><p>The PI3K/AKT is one of the most important signaling pathways that mediates the process of EMT through (i) direct activation of transcription factors (twist 1, 2) which increases the expression of mesenchymal markers (N-cadherin), decreases the expression of epithelial markers (E-cadherin, claudin, occluding) and upregulates <italic>AKT</italic> gene, which is involved in drug resistance in breast cancer, (ii) increased activity of integrin-linked kinase (which downregulates E-cadherin) and (iii) activation of matrix-degrading proteases (MMP2, MMP9) [<xref rid="B55-ijms-21-00401" ref-type="bibr">55</xref>,<xref rid="B174-ijms-21-00401" ref-type="bibr">174</xref>]. Moreover, other factors are also involved in EMT activation such as growth factors (FGF, EGF, TGF-β), adhesion molecules (ICAM-1), signaling pathways (NF-κB, Wnt/β-catenin, Notch), overexpression of EMT transcription factors (slug, snail) and members of heat-shock proteins family (such as glucose regulated protein 78 (GRP78)) [<xref rid="B53-ijms-21-00401" ref-type="bibr">53</xref>,<xref rid="B172-ijms-21-00401" ref-type="bibr">172</xref>,<xref rid="B174-ijms-21-00401" ref-type="bibr">174</xref>,<xref rid="B176-ijms-21-00401" ref-type="bibr">176</xref>]. Notably, due to the correlation between drug resistance and acquisition of EMT phenotype (i.e., EMT modified cells appear similar to CSC as a result of their high levels of ABC transporters), targeting EMT might represent a new toll to circumvent drug resistance in cancer [<xref rid="B177-ijms-21-00401" ref-type="bibr">177</xref>]. </p></sec><sec id="sec2dot10-ijms-21-00401"><title>2.10. Epigenetic Variations</title><p>The main types of epigenetic mechanisms involved in cancer drug resistance are DNA methylation and histone alterations [<xref rid="B54-ijms-21-00401" ref-type="bibr">54</xref>]. Aberrant DNA methylation is associated with genes encoding for proteins involved in cell differentiation, proliferation, apoptosis (MAPK, VEGF, Wnt/β-catenin, p15, p16, p53, APAF-1) or genes encoding drug transporters (MDR1) [<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>,<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. Moreover, epigenetic mechanisms can also affect the DNA repair system, since hypermethylation of hMLH1 gene is responsible for colorectal cancer [<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>]. </p><p>Recently several studies revealed the important role of epigenetic regulator, polycomb repressive complex 2 catalytic component enhancer of zeste homolog 2 (EZH2), in neoplastic development and drug resistance in many types of cancer (gastric, lung, hepatic) [<xref rid="B178-ijms-21-00401" ref-type="bibr">178</xref>]. According to Chang and co-workers, overexpression of EZH2 upregulates EMT transition and decreases sensitivity to several chemotherapeutic agents (i.e., cisplatin) [<xref rid="B179-ijms-21-00401" ref-type="bibr">179</xref>]. Since epigenetic alterations might represent a viable anticancer and anti-drug resistance target, a large series of DNA methylation or histone deacetylases inhibitors have been generated. These comprise nucleoside analogs (i.e., 5-Azacytidine, zebularine) or non-nucleoside analogs (i.e., hydralazine) against DNA methylation or short fatty acids, hydroxy-cinnamic acids, cyclic tetrapeptides and benzamide against histone deacethylases [<xref rid="B180-ijms-21-00401" ref-type="bibr">180</xref>,<xref rid="B181-ijms-21-00401" ref-type="bibr">181</xref>]. Notably, a disadvantage of the drugs that act against epigenetic modification consists in lack of specificity. However, their systemic administration can activate oncogenes, which are involved in promotion of malignancy [<xref rid="B182-ijms-21-00401" ref-type="bibr">182</xref>]. Besides the epigenetic inhibitors used to overcome drug resistance, Baylin proposed a mechanism based on withdrawal of the chronical drug administration, which in turn will reduce the number of cancer cells with epigenetic modifications and will increase the heterogeneity of the tumor cells, making them sensitive to other anticancer therapies [<xref rid="B183-ijms-21-00401" ref-type="bibr">183</xref>]. All these studies and challenges make epigenetic alterations attractive candidates for further therapeutic applications. </p></sec><sec id="sec2dot11-ijms-21-00401"><title>2.11. Dysregulation of microRNA (miRNAs)</title><p>miRNAs are a family of small single-stranded non-coding RNAs of 20–25 nucleotides. Usually, their main function is downregulation of gene expression at post-transcriptional level [<xref rid="B184-ijms-21-00401" ref-type="bibr">184</xref>]. The dysregulation of miRNAs in cancer cells can lead to drug resistance by abnormal modulation of genes expression responsible for MDR, such as (i) ABC transporter genes, (ii) genes related to apoptosis and autophagy, (iii) drug metabolism genes, (iv) DNA repair or (iv) redox system relating genes [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>,<xref rid="B184-ijms-21-00401" ref-type="bibr">184</xref>]. </p><p>Regarding miRNAs role in regulation of MDR transporters, it was shown that downregulation of miR-38 and miR-200c led to doxorubicin resistance in breast cancer cells, through upregulation of BCRP protein [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. Downregulation of miR-7 led to drug resistance in lung cancer, through upregulation of MRP1 [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. Upregulation of several miRNA (miR-16, miR-17) sensitize resistant lung cancer cells to paclitaxel treatment through inhibition of beclin 1 and Bcl-2, promoting apoptosis. Moreover, it was shown that downregulation of miR-17-5p sensitizes colorectal cancer cells to chemotherapeutic agents (5-FU), through increased activity of PTEN [<xref rid="B93-ijms-21-00401" ref-type="bibr">93</xref>]. </p><p>miRNAs are also involved in chemotherapeutic agents metabolism; for example miR-27b negatively regulates CYP1B1 expression, while miR-892a regulates CYP1A1 activity and sensitize cells to a wide spectrum of chemotherapeutic agents [<xref rid="B184-ijms-21-00401" ref-type="bibr">184</xref>]. Moreover, it was shown that miR-27a contributes to cisplatin resistance by modulation of GSH biosynthesis [<xref rid="B184-ijms-21-00401" ref-type="bibr">184</xref>]. Several miRNAs modulate chemosensitivity of cancer cells through interfering with DNA repair mechanisms. For example, over–expression of miR-21 downregulated the expression of mismatch repair (MMR) proteins, thus reducing the therapeutic effect of 5-FU in colorectal cancer cells [<xref rid="B184-ijms-21-00401" ref-type="bibr">184</xref>]. In conclusion, miRNAs can serve as therapeutic agents for overcoming MDR [<xref rid="B90-ijms-21-00401" ref-type="bibr">90</xref>].</p></sec><sec id="sec2dot12-ijms-21-00401"><title>2.12. Modulation of Reactive Oxygen Species (ROS)</title><p>Modulating reactive oxygen species (ROS) represent a challenging approach to reverse MDR in cancer cells. It is well known that ROS level and the activity of antioxidant enzymes (glutathione peroxidase—GPX, glutathione-S-transferase, catalase, superoxide-dismutase—SOD, hem-oxygenase 1, NAD(P)H quinone oxidoreductase 1, glutamate/cysteine antiporter solute carrier family 7 member 11—xCT, etc.) in MDR cancer cells are overexpressed compared to non-MDR cells [<xref rid="B185-ijms-21-00401" ref-type="bibr">185</xref>,<xref rid="B186-ijms-21-00401" ref-type="bibr">186</xref>]. Overexpression of ROS facilitate MDR, through upregulation of different pathways (i.e., MAPK, JNK, Nf-kB, PI3K/AKT, Keap1-Nrf2-ARE) [<xref rid="B55-ijms-21-00401" ref-type="bibr">55</xref>,<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>,<xref rid="B185-ijms-21-00401" ref-type="bibr">185</xref>]. According to recent research, cancer cells expressing Nrf2 are resistant to chemotherapeutic agents (doxorubicin, etoposide, cisplatin) by increasing GSH production and upregulation of MRP1 [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>]. According to Zeng et al., the transcriptional factor src/STAT3 also promotes MDR in cancer cells by promoting antioxidant feedback, through increased expression of GPX and SOD2 activity [<xref rid="B187-ijms-21-00401" ref-type="bibr">187</xref>].</p><p>Usually ROS are produced by the highly reactive mitochondrial electron transport chain of aerobic respiration, oxido-reductase enzymes (xanthinoxidase, cyclooxygenase, NADPH oxidases—NOXs, etc.) or metal catalyzed oxidation [<xref rid="B185-ijms-21-00401" ref-type="bibr">185</xref>]. Recent research has shown that mitochondrial functions are altered in cancer cells, due to imbalance between fusion/fission dynamics and increased mitophagy, which grants a rapid clearance of chemotherapeutic agents, increases ABC transporters activity (by providing ATP) and modifies mitochondrial membrane potential [<xref rid="B75-ijms-21-00401" ref-type="bibr">75</xref>].</p><p>Several agents (current in preclinical or clinical studies) are involved in modulation of ROS in MDR by (i) disrupting mitochondrial electron transport chain (elesclomol), (ii) inhibition of NOXs (ampelopsin), (iii) depletion of intracellular GSH (APR246), (iv) inhibition of xCT, required for GSH synthesis (erastin, vorinostat) or (v) inhibition of Nrf2 pathway (camptothecin) [<xref rid="B185-ijms-21-00401" ref-type="bibr">185</xref>].</p></sec></sec><sec id="sec3-ijms-21-00401"><title>3. Role of Polyphenols in MDR</title><sec id="sec3dot1-ijms-21-00401"><title>3.1. In Vitro Studies </title><sec id="sec3dot1dot1-ijms-21-00401"><title>3.1.1. Flavonoid Compounds</title><sec><title>Flavones </title><p>Flavonoid compounds were intensively tested for their capacity to enhance the effect of anti-cancer drugs and to combat MDR in different types of cancers. An experiment conducted on CD44<sup>+</sup> prostate cancer stem cells provided relevant information that <italic>apigenin</italic> co-administrated with cisplatin stimulated the therapeutic effects of cisplatin by inducing a series of modulatory effects on the expression of essential proteins and enzymes [<xref rid="B188-ijms-21-00401" ref-type="bibr">188</xref>]. The mechanism of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was studied in conjunction with flavonoids as potentiating agents, due to the high occurrence of TRAIL resistance in various cancer types. In this regard, Yang et al. demonstrated that <italic>wagonin</italic> showed the capacity to enhance apoptosis mediated by TRAIL in vitro through downregulating the expression levels of anti-apoptotic proteins [<xref rid="B41-ijms-21-00401" ref-type="bibr">41</xref>]. </p><p>According to Rao et al., <italic>luteolin</italic> overcomes MDR in breast cancer mitoxantrone resistant cells through increased apoptosis, DNA damage, activation of ATR/Chk2/p53 signaling pathways, inhibition of NF-κB signaling pathway and depletion of anti-apoptotic proteins [<xref rid="B189-ijms-21-00401" ref-type="bibr">189</xref>]. </p><p>Nucleoid factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates genes responsible for the synthesis of endogenous antioxidants (hemeoxygenase-1—HO-1), transporters (MRP1, MRP2) and detoxifying enzymes (glutathione-S-transferase) [<xref rid="B190-ijms-21-00401" ref-type="bibr">190</xref>]. Recent research have demonstrated that Nrf2 is overexpressed in MDR cancer [<xref rid="B190-ijms-21-00401" ref-type="bibr">190</xref>]. According to recent data, co-treatment of breast and lung cancer cells with <italic>luteolin</italic> and chemotherapeutic agents (oxaliplatin, doxorubicin, bleomycin) resulted in a higher percentage of cells death. The suggested mechanisms involve downregulation of <italic>NRF2</italic> gene expression (MDR and HO1) and increased sensitization of the cells to chemotherapeutic treatment [<xref rid="B190-ijms-21-00401" ref-type="bibr">190</xref>,<xref rid="B191-ijms-21-00401" ref-type="bibr">191</xref>].</p></sec><sec><title>Flavonols</title><p><italic>Quercetin</italic> was found to suppress effects of P-gp in breast cancer cells and to increase the disappearance of breast cancer stem cells. In this case, doxorubicin-resistant MCF-7 cells were evaluated for how they respond to different drugs (doxorubicin, paclitaxel and vincristine) in conjunction with quercetin. It was found that the co-administration of these drugs with quercetin potentiated their chemotherapeutic effect [<xref rid="B192-ijms-21-00401" ref-type="bibr">192</xref>]. The potential of quercetin to reverse the MDR process through the inactivation of P-gp was also revealed on vincristine resistant human colorectal adenocarcinoma Caco-2 cells [<xref rid="B193-ijms-21-00401" ref-type="bibr">193</xref>]. Another study performed on Caco-2 cells showed that quercetin as well as naringenin and genistein manifested inhibitory effects on cell elimination of cimetidine through P-gp activity [<xref rid="B194-ijms-21-00401" ref-type="bibr">194</xref>]. Downregulation of P-gp by quercetin and other flavonoids such as naringenin, biochanin A, silymarin, genistein was successfully demonstrated in daunomycin resistant MCF-7 breast cancer cell lines. It was shown that these compounds not only stimulated the accumulation of the drug, but also substantially reduced its efflux [<xref rid="B195-ijms-21-00401" ref-type="bibr">195</xref>]. </p><p>It was also observed that <italic>fisetin</italic>—another dietary flavonoid compound—changed the MDR course of action leading to the chemosensitizing effects on colorectal cancer cells resistant to common chemotherapeutic drugs. Co-administration of fisetin with irinotecan and oxaliplatin induced apoptosis in cultured cells by increasing the activity of caspase-8 and caspase-3. Furthermore, this combined treatment triggered the efflux of cytochrome C and considerably reduced the phosphorylation mechanisms of IGF1R and AKT [<xref rid="B196-ijms-21-00401" ref-type="bibr">196</xref>].</p></sec><sec><title>Flavanones</title><p><italic>Hesperidin</italic> (hesperitin rutinoside) was able to increase the sensitivity of breast resistant cancer cells to doxorubicin, through decreased expression of P-gp [<xref rid="B197-ijms-21-00401" ref-type="bibr">197</xref>]. Moreover, El-Readi M.Z. and his co-workers have shown that hesperidin had a significantly higher inhibitory effect of P-gp than nobiletin and stigmasterol but lower effect than limonin in overcoming MDR in colorectal cancer cells [<xref rid="B198-ijms-21-00401" ref-type="bibr">198</xref>].</p></sec><sec><title>Flavan-3-ols</title><p>Impeding DNA damage repair processes through dietary flavonoids was also shown to be a successful endeavor in combating chemoresistance in cancer. It was found that quercetin, <italic>catechin</italic> and fisetin intensified the sensitivity of breast cancer cells to cisplatin by inhibiting ATR-Chk1 pathway [<xref rid="B199-ijms-21-00401" ref-type="bibr">199</xref>]. Green tea polyphenols have also shown inhibitory properties towards efflux pumps (P-gp) [<xref rid="B200-ijms-21-00401" ref-type="bibr">200</xref>]. The inhibitory effect decreased as follows epigallocatechingallate > epigallocatechin > catechin > epicatechin [<xref rid="B201-ijms-21-00401" ref-type="bibr">201</xref>]. EGCG induces the reversal of MDR by regulating detoxification mechanisms and downregulation of Nrf2 pathway in breast cancer cells resistant to tamoxifen [<xref rid="B202-ijms-21-00401" ref-type="bibr">202</xref>]. Moreover, according to La X. and co-workers, EGCG enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting GRP78/NF-κB/miR-155-5p/MDR1 pathway [<xref rid="B203-ijms-21-00401" ref-type="bibr">203</xref>]. Green tea polyphenols (EGCG) associated with quercetin enhanced the therapeutic effect of docetaxel in metastatic and castration-resistant prostate cancer through downregulation of MRP expression, decreased percentage of CD44<sup>+</sup>/CD24<sup>−</sup> stem-like cells and induced inhibition of PI3K/AKT/STAT3 signaling pathway [<xref rid="B204-ijms-21-00401" ref-type="bibr">204</xref>]. Receptor tyrosine kinase signaling pathway has been reported to promote cell proliferation, inhibit apoptosis and to play a major role in MDR. EGCG was shown to reverse MDR in cisplatin resistant lung cancer through downregulation of several receptor tyrosine kinases [<xref rid="B205-ijms-21-00401" ref-type="bibr">205</xref>].</p></sec><sec><title>Isoflavones</title><p><italic>Genistein</italic>—an isoflavone found mainly in soybeans—overcomes chemoresistance to doxorubicin in MDR breast cancer cells through increased accumulation of the chemotherapeutic agent, promotion of apoptosis and suppression of HER2 mRNA expression. However, it had no effect on MDR-1 expression [<xref rid="B206-ijms-21-00401" ref-type="bibr">206</xref>]. According to Li and co-workers (2005), genistein pre-treatment of prostate and lung cancer cells inhibits NF-κB activity and contributes to increased growth inhibition and apoptosis induced by cisplatin and docetaxel [<xref rid="B207-ijms-21-00401" ref-type="bibr">207</xref>]. Another isoflavone, <italic>daidzein</italic>, found in soybeans, inhibited BCRP and MRP1/2 drug transporters, therefore sensitizing breast cancer cells to chemotherapeutic agents (mitoxantrone, doxorubicin) [<xref rid="B208-ijms-21-00401" ref-type="bibr">208</xref>].</p></sec></sec><sec id="sec3dot1dot2-ijms-21-00401"><title>3.1.2. Non-Flavonoid Compounds</title><sec><title>Stilbenes </title><p><italic>Resveratrol</italic> is a polyphenol commonly found in red wine and grapes that possesses strong antioxidant and anti-aging properties [<xref rid="B209-ijms-21-00401" ref-type="bibr">209</xref>]. According to several studies co-administration of resveratrol and other therapeutic agents (paclitaxel, docetaxel, doxorubicin, rapamycin, gefitinib) reversed MDR in breast, lung and colorectal cancer through enhancement of chemotherapeutic agents bioavailability, increase drug retention time, stimulation of pro-apoptosis mechanisms, cell cycle arrest or downregulation of ABC transporters [<xref rid="B209-ijms-21-00401" ref-type="bibr">209</xref>,<xref rid="B210-ijms-21-00401" ref-type="bibr">210</xref>,<xref rid="B211-ijms-21-00401" ref-type="bibr">211</xref>,<xref rid="B212-ijms-21-00401" ref-type="bibr">212</xref>,<xref rid="B213-ijms-21-00401" ref-type="bibr">213</xref>,<xref rid="B214-ijms-21-00401" ref-type="bibr">214</xref>]. </p></sec><sec><title>Lignans </title><p>Co-encapsulation of <italic>honokiol</italic> (a lignan isolated from the bark, stem and leaves of <italic>Magnolia</italic> sp.) and paclitaxel in pH-sensitive polymeric micelles suppressed MDR in breast cancer through downregulation of P-gp expression and increase of plasma membrane fluidity [<xref rid="B43-ijms-21-00401" ref-type="bibr">43</xref>]. Moreover, honokiol radiosensitizes colorectal cancer cells due to higher levels of apoptosis (caspase-3 activation, increased Bax/Bcl-2 ratio) and reduced expression of cyclin A1 and D1 [<xref rid="B215-ijms-21-00401" ref-type="bibr">215</xref>]. </p><p>Other lignans, such as <italic>schizandrin A,</italic> isolated from <italic>Schisandra chinensis</italic> fruits enhanced chemosensitivity of colorectal carcinoma cells to 5-FU through upregulation of miR-195. In addition, upregulation of miR-195 inactivated NF-κB and PI3K/AKT signaling pathways [<xref rid="B48-ijms-21-00401" ref-type="bibr">48</xref>]. <italic>Silybin</italic> is the major active constituent of silymarin (a mixture of flavonolignans) from milk thistle fruits. According to Molavi et al., silybin treatment of breast cancer cells resistant to doxorubicin/paclitaxel, sensitized cells to chemotherapeutic agents by suppressing the key oncogenic pathways STAT3, AKT and ERK [<xref rid="B46-ijms-21-00401" ref-type="bibr">46</xref>]. According to recent research, a combination of flaxseed lignan (<italic>secoisolariciresinol</italic>) and its metabolite (<italic>enterolactone</italic>) enhanced the cytotoxic effects of docetaxel, carboplatin and doxorubicin in metastatic breast cancer cell lines, likely by inhibition of fatty acid synthase [<xref rid="B47-ijms-21-00401" ref-type="bibr">47</xref>].</p></sec><sec><title>Ellagitannins</title><p>Ellagitannins and their metabolite, <italic>ellagic</italic> acid, overcome MDR in cancer, by inhibition of P-gp, MRP and BCRP proteins [<xref rid="B216-ijms-21-00401" ref-type="bibr">216</xref>]. Ellagic acid sensitizes human colorectal cancer cells to 5-FU treatment through increased Bax/Bcl-2 ratio, activation of caspase-3 and loss of mitochondrial potential [<xref rid="B217-ijms-21-00401" ref-type="bibr">217</xref>]. Ellagitannins and their metabolites play a key role for overcoming MDR in breast resistant cancer cell line [<xref rid="B218-ijms-21-00401" ref-type="bibr">218</xref>]. Berdowska et al. have studied the effect of several ellagitannins (agrimoniin, sanguiin-H6, tellimagrandin I, rugosins A, D and pedunculagin) on doxorubicin-resistant breast cancer cells. Among the tested compounds, only sanguiin-H6 showed cytotoxic effects towards resistant MCF-7 cancer cells, probably due to the release of sanguisorbic acid dilactone, which inhibited ABC transporters, thus diminishing the ability of cells to extrude other products of sanguiin-H6 hydrolysis (ellagic acid, depsides), with cytotoxic effects [<xref rid="B218-ijms-21-00401" ref-type="bibr">218</xref>]. </p></sec><sec><title>Hydroxy-Benzoic Acids</title><p>Among phenolcarboxylic acids, <italic>gallic acid</italic> induces apoptosis, enhances the anticancer effect of cisplatin in human lung cancer and reverse MDR [<xref rid="B219-ijms-21-00401" ref-type="bibr">219</xref>]. Mechanisms responsible for above-mentioned effects include induction of apoptosis by ROS generation, disruption of mitochondrial membrane potential, increase in the expression of Bax, APAF1, DIABLO and p53 and decrease in the expression of inhibitor of apoptosis protein 3 [<xref rid="B219-ijms-21-00401" ref-type="bibr">219</xref>]. In addition, association between gallic acid and ECGC attenuated MDR in doxorubicin-resistant breast cancer cells through a concentration-dependent inhibition of metalloproteinases (MMP-2 and MMP-9). It is well known that metalloproteinases are involved in the degradation of extracellular matrix by metastatic cancer cells [<xref rid="B220-ijms-21-00401" ref-type="bibr">220</xref>]. Another mechanism involved in gallic acid overcoming MDR is the inhibition of Src/STAT3-mediated signaling and the decrease in the expression of STAT3-regulated tumor-promoting genes, therefore inducing apoptosis and cell cycle arrest. It is well known that activation of STAT3 signaling pathway is associated with resistance to tyrosine kinase inhibitors, which are frequently used in lung cancer treatment [<xref rid="B221-ijms-21-00401" ref-type="bibr">221</xref>]. </p></sec><sec><title>Hydroxy-Cinnamic Acids</title><p><italic>Ferulic acid</italic> and <italic>caffeic acid</italic> isolated from foxtail millet (a Chinese cereal food) reverse MDR in human colorectal cancer cells through decreased expression of MRP1, P-gp and BRCP [<xref rid="B222-ijms-21-00401" ref-type="bibr">222</xref>]. </p><p><italic>Caffeic acid phenetyl ester (CAPE)</italic> is a strong inhibitor of human breast cancer stem cells by inhibition of cells’ renewal, progenitor formation and decrease in CD44<sup>+</sup> cells content. CD44<sup>+</sup> cells are responsible for tumor formation from a very few cells and are resistant to chemotherapy [<xref rid="B223-ijms-21-00401" ref-type="bibr">223</xref>]. According to Khoram et al., CAPE augments the radio sensibility of breast cancer cells [<xref rid="B224-ijms-21-00401" ref-type="bibr">224</xref>]. Moreover, CAPE shows beneficial effect in overcoming MDR in lung and prostate cancer through depleting intracellular stores of GSH (reduced glutathione), blocking NF-κB pathway, downregulation of apoptosis inhibitors (cIAP1, cIAP-2 and XIAP) and claudin-2 expression [<xref rid="B225-ijms-21-00401" ref-type="bibr">225</xref>,<xref rid="B226-ijms-21-00401" ref-type="bibr">226</xref>]. According to recent research, treatment of lung adenocarcinoma derived stem-like cells with <italic>cinnamic acid</italic> diminishes their proliferation and facilitates their differentiation into CD133 (a marker used for isolation of cancer stem cell population mainly from carcinomas) negative cells [<xref rid="B227-ijms-21-00401" ref-type="bibr">227</xref>]. </p></sec><sec><title>Other Compounds</title><p><italic>Curcumin</italic> is the major active substance of the culinary spice turmeric (<italic>Curcuma longa</italic>) and has strong antioxidant, anti-inflammatory and anti-cancer effects [<xref rid="B34-ijms-21-00401" ref-type="bibr">34</xref>,<xref rid="B50-ijms-21-00401" ref-type="bibr">50</xref>,<xref rid="B228-ijms-21-00401" ref-type="bibr">228</xref>,<xref rid="B229-ijms-21-00401" ref-type="bibr">229</xref>]. Curcumin has been reported to attenuate oxaliplatin and 5-fluorouracil (5-FU) acquired resistance in colorectal and breast cancer cells through inhibition of NF-κB signaling cascade [<xref rid="B230-ijms-21-00401" ref-type="bibr">230</xref>,<xref rid="B231-ijms-21-00401" ref-type="bibr">231</xref>]. Moreover, association between curcumin and oxaliplatin downregulated the expression of NF-κB regulated gene products involved in inflammation (CXC-chemokines, which are highly overexpressed due to acquired resistance) and decreased the levels of p65 [<xref rid="B230-ijms-21-00401" ref-type="bibr">230</xref>]. Recent research has shown that a curcumin-derivative (difluorinated curcumin) inhibits 5-FU and oxaliplatin resistant colorectal cancer cells through downregulation of miR-21. miR-21 downregulates PTEN, a tumor suppressor gene. Decreased activity of PTEN is involved in resistance to conventional therapy and recurrence of cancer initial treatment [<xref rid="B232-ijms-21-00401" ref-type="bibr">232</xref>]. Moreover, PTEN downregulates Nrf2 activity and autophagy, which have been reported to play a protective role in cisplatin induced apoptotic cell death [<xref rid="B233-ijms-21-00401" ref-type="bibr">233</xref>]. According to Gu et al., nanomicelles loaded with doxorubicin and curcumin alleviate MDR in lung cancer, due to increased cellular uptake of chemotherapeutic agents [<xref rid="B234-ijms-21-00401" ref-type="bibr">234</xref>]. According to recent studies, curcumin reverses cisplatin resistance and promotes human lung adenocarcinoma apoptosis through increased apoptosis and down-regulation of HIF-1α [<xref rid="B235-ijms-21-00401" ref-type="bibr">235</xref>]. It has been shown that curcumin inhibits mammalian target of rapamycin (mTOR)—a serin/threonine kinase—and downregulates the key epigenetic regulator enhancer of zeste homolog 2 (EZH2) in tamoxifen resistant breast cancer cells [<xref rid="B236-ijms-21-00401" ref-type="bibr">236</xref>]. According to Thulasiraman, curcumin also restores sensitivity to retinoic acid in triple negative breast cancer cells by suppressing the expression level of fatty acid-binding protein 5 (FBAP5) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ) [<xref rid="B237-ijms-21-00401" ref-type="bibr">237</xref>]. The combination of curcumin with other phenolic compounds (such as EGCG) showed synergistic effects in overcoming doxorubicin-resistant tumor breast cells through caspase-dependent apoptotic signaling pathways, downregulation of anti-apoptotic Bcl-2 and survivin, and enhancement of cellular incorporation of curcumin [<xref rid="B238-ijms-21-00401" ref-type="bibr">238</xref>].</p><p><italic>Gingerol</italic> represents the main active substance from dry or fresh ginger roots, a popular spice widely used in many diseases (nausea, diarrhea and cancer) [<xref rid="B51-ijms-21-00401" ref-type="bibr">51</xref>]. According to Liu Chin-Ming and co-workers, 6-gingerol and 10-gingerol inhibited the proliferation of docetaxel resistant human prostate cancer cells through downregulation of MRP1 and GST [<xref rid="B51-ijms-21-00401" ref-type="bibr">51</xref>]. According to recent research, 6-gingerol shows high anticancer potency in cyclophosphamide, 5-FU and doxorubicin-resistant breast cancer MCF-7 cell line, due to its antioxidant activity and regulation of different cellular pathways (Wnt-β catenin or glycogen synthase kinase 3—GSK3) [<xref rid="B239-ijms-21-00401" ref-type="bibr">239</xref>].</p><p>In conclusion, recent in vitro studies (<xref rid="ijms-21-00401-t002" ref-type="table">Table 2</xref>) have shown that phenolic compounds overcome MDR in different types of cancer (breast, lung, prostate, colorectal) by inhibition of efflux pumps (P-gp, MRP1, BCRP), increased apoptosis and decreased proliferation of cancer stem cells, increased cellular uptake of chemotherapeutic agents, downregulation of miR-27a, miR-195, miR-21, inactivation of DNA damage repair, decreased expression of anti-apoptotic proteins and modulation of important signaling pathways involved in carcinogenesis (PI3/Akt, Wnt-β catenin, GSK-3, NF-κB, mTOR, Nrf2, ERK, JNK, etc.). </p><p>Considering the evidence provided by in vitro studies, continuous pharmacological research (pre-clinical and clinical studies) is needed in order to verify the potential beneficial effects of polyphenols in vivo and to discover new mechanisms of action for overcoming MDR.</p></sec></sec><sec id="sec3dot1dot3-ijms-21-00401"><title>3.1.3. Synergic and Pleiotropic Activity of Polyphenols </title><p>Recent data support the hypothesis that combined drug therapy might be more efficient than monotherapy (“one drug-one target” therapy). The synergistic effects of combined administration of polyphenols appears mainly at a molecular level, since they influence different pathways involved in multidrug resistance. For example, association between curcumin and EGCG showed synergistic effect in overcoming doxorubicin resistance in tumor breast cancer cells [<xref rid="B238-ijms-21-00401" ref-type="bibr">238</xref>]. The synergistic effect occurs due to inhibition of P-gp expression by EGCG, thus increasing the incorporation of curcumin in breast cancer cells, leading to enhancement of apoptosis and regulation of apoptosis proteins [<xref rid="B238-ijms-21-00401" ref-type="bibr">238</xref>]. A similar effect was observed for the association between EGCG and gallic acid in multidrug resistant MCF7/DOX breast cancer cells [<xref rid="B220-ijms-21-00401" ref-type="bibr">220</xref>]. The inhibitory effect of EGCG upon P-gp increases gallic acid concentration in cancer cells leading to inhibition of matrix metaloproteinases (MMP-2, MMP-9). Regarding the combination of EGCG and quercetin in docetaxel resistant prostate cancer cells [<xref rid="B204-ijms-21-00401" ref-type="bibr">204</xref>], both compounds are strong inhibitors of P-gp [<xref rid="B240-ijms-21-00401" ref-type="bibr">240</xref>]. Consequently, both compounds have increased concentrations in prostate cancer cells and act by inhibition of PI3K/AKT, STAT3 signaling pathways and decreased cancer stem cells activity [<xref rid="B204-ijms-21-00401" ref-type="bibr">204</xref>]. Since the data regarding the interactions between polyphenols in MDR models are promising but limited, this might represent starting points for future studies. </p><p>The pleiotropic effect of the polyphenols has already been acknowledged in the scientific publications [<xref rid="B241-ijms-21-00401" ref-type="bibr">241</xref>,<xref rid="B242-ijms-21-00401" ref-type="bibr">242</xref>]. Based on the reported data, polyphenols overcome multidrug resistance by affecting different pathways in different types of cancer [<xref rid="B243-ijms-21-00401" ref-type="bibr">243</xref>]. For example: (i) quercetin increases apoptosis, inhibits angiogenesis (in colorectal cancer cells) [<xref rid="B244-ijms-21-00401" ref-type="bibr">244</xref>], inhibits P-gp activity (in breast cancer cells) [<xref rid="B245-ijms-21-00401" ref-type="bibr">245</xref>]; (ii) curcumin down-regulates P-gp and Hsp27, induces autophagy, reduces the markers of cancer stem cells (colon cancer cells) [<xref rid="B246-ijms-21-00401" ref-type="bibr">246</xref>,<xref rid="B247-ijms-21-00401" ref-type="bibr">247</xref>,<xref rid="B248-ijms-21-00401" ref-type="bibr">248</xref>], inhibits the activity of ABCB4 pump, inhibits epithelial-mesenchymal transition (breast cancer cells) [<xref rid="B249-ijms-21-00401" ref-type="bibr">249</xref>,<xref rid="B250-ijms-21-00401" ref-type="bibr">250</xref>], inhibits JNK pathway, suppresses invasion by inhibition of STAT3 activity (prostate cancer) [<xref rid="B251-ijms-21-00401" ref-type="bibr">251</xref>,<xref rid="B252-ijms-21-00401" ref-type="bibr">252</xref>] or induces apoptosis (lung cancer cells) [<xref rid="B253-ijms-21-00401" ref-type="bibr">253</xref>]; (iii) resveratrol down-regulates the expression of survivin (in prostate cancer cells) [<xref rid="B254-ijms-21-00401" ref-type="bibr">254</xref>] and inhibits MAPK kinase in prostate and lung cancer cells [<xref rid="B255-ijms-21-00401" ref-type="bibr">255</xref>]; (iv) EGCG inhibits drug efflux (in prostate cancer cells), increases drug concentration in cancer cells by inhibition of enzymes involved in drug metabolism (in colorectal cancer cells), increased ROS production (in colorectal cancer cells)—thus it is responsible for AMPK activation—and induces epigenetic restoration of estrogen receptors through histone modifications (in breast cancer cells) [<xref rid="B256-ijms-21-00401" ref-type="bibr">256</xref>]. Nevertheless, based on reported data, some polyphenols can target the same molecule in different cancer cell lines. For instance, resveratrol can downregulate P-gp in breast, lung and colorectal cancer cells [<xref rid="B210-ijms-21-00401" ref-type="bibr">210</xref>,<xref rid="B211-ijms-21-00401" ref-type="bibr">211</xref>,<xref rid="B212-ijms-21-00401" ref-type="bibr">212</xref>]. Taken together these data suggest that polyphenols are able to modulate different signaling pathways being cell-line-specific and to target certain molecules independent of cell type (<xref rid="ijms-21-00401-t002" ref-type="table">Table 2</xref>).</p></sec></sec><sec id="sec3dot2-ijms-21-00401"><title>3.2. In Vivo and Clinical Studies </title><sec id="sec3dot2dot1-ijms-21-00401"><title>3.2.1. Flavonoid Compounds</title><sec><title>Flavones and Flavonols </title><p>Shin et al. published a study centered on the co-administration of tamoxifen with <italic>quercetin</italic> in rats, showing great evidence of the inhibition of P-gp, MRP2 and BCPR, as well as relevant data, which support the antioxidant property of quercetin through the reduction of CYP3A4 activity [<xref rid="B257-ijms-21-00401" ref-type="bibr">257</xref>]. Experiments on animal models confirm the suppressing function of <italic>quercetin</italic> on ABC proteins involved in MDR. </p><p>Co-encapsulation of <italic>quercetin</italic> and doxorubicin in biotin receptor-targeting nanoparticles was more effectively taken up with less efflux due to downregulation of P-gp expression in nude mice bearing MCF-7 breast cancer cells resistant to adriamycin (doxorubicin) [<xref rid="B258-ijms-21-00401" ref-type="bibr">258</xref>]. According to et al., applying <italic>wogonin</italic> and TRAIL in a mouse model of lung cancer enhances TRAIL’s antitumor activity and overcomes MDR through augmentation of apoptosis and decreased the expression of anti-apoptotic proteins (survivin, XIAP, etc.) [<xref rid="B41-ijms-21-00401" ref-type="bibr">41</xref>]. </p><p><italic>Fisetin</italic> showed promising effects in a mouse model of lung cancer and prevented MDR through increased apoptosis and downregulation of AKT and IGFR1 phosphorylation levels [<xref rid="B196-ijms-21-00401" ref-type="bibr">196</xref>].</p><p><italic>Luteolin</italic>, another flavonoid, was analyzed for its potential beneficial role in reversing MDR in cancer. For this purpose, a group of researchers took into consideration the analysis of xenograft tumors of lung cancer, which were treated with luteolin, erlotinib and cisplatin for 15 days. They concluded that the group of mice treated with luteolin and cisplatin showed the most relevant reduction in the tumor mass. Moreover, luteolin was shown to sensitize tumor cells to erlotinib through downregulation of EGFR/PI3K/AKT/mTOR signaling pathway and increased apoptosis [<xref rid="B259-ijms-21-00401" ref-type="bibr">259</xref>].</p></sec><sec><title>Flavan-3-ols</title><p>Combining <italic>EGCG</italic> with paclitaxel induced significant cell apoptosis in a murine model of breast carcinoma. Moreover, EGCG overcame MDR to paclitaxel by inhibiting GRP78 expression and inhibition of JNK phosphorylation [<xref rid="B260-ijms-21-00401" ref-type="bibr">260</xref>]. In a rat model of breast carcinogenesis application of EGCG overcame MDR to paclitaxel through increased apoptosis, decrease of cancer stem cells, decreased VEGF expression and MMP-2 activity [<xref rid="B261-ijms-21-00401" ref-type="bibr">261</xref>].</p></sec><sec><title>Isoflavones </title><p>The potential of <italic>genistein</italic> to cause inhibition of MDR in lung cancer was intensively studied. One representative case is the assessment of the genistein-cisplatin treatment of non-small cell lung cancer (NSCLC) in xenografted mice models, in order to prove the sensitization of drug-resistant cancer cells via enhanced activity of caspase-3, 8, 10 and suppression of PI3K/AKT activity [<xref rid="B262-ijms-21-00401" ref-type="bibr">262</xref>]. The property of genistein to sensitize NSCLC cells was demonstrated for another chemotherapeutic agent, gefitinib. In this respect, it was acknowledged that the combinatory treatment using genistein and gefitinib increased apoptosis and downregulated EGFR and mTOR signaling pathways [<xref rid="B263-ijms-21-00401" ref-type="bibr">263</xref>].</p></sec></sec><sec id="sec3dot2dot2-ijms-21-00401"><title>3.2.2. Non-Flavonoid Compounds</title><sec><title>Stilbenes</title><p>Co-encapsulation of resveratrol and paclitaxel in a PEGylated liposome showed effective inhibitory effects in drug-resistant breast tumors in mice through increased cellular uptake of paclitaxel and decreased activity of efflux pumps (MRP, P-gp) [<xref rid="B264-ijms-21-00401" ref-type="bibr">264</xref>]. According to Yang et al., resveratrol sensitized colorectal cancer cells to oxaliplatin, mainly by upregulation of miR-34c in correlation with increased levels of p53 and reduction of tumor growth in xenograft experiments [<xref rid="B265-ijms-21-00401" ref-type="bibr">265</xref>]. Resveratrol significantly inhibited MDR in nude mouse models inoculated with human non-small cell lung cancer cells by downregulation of survivin and activation of caspase-3 [<xref rid="B266-ijms-21-00401" ref-type="bibr">266</xref>].</p></sec><sec><title>Hydroxy-Cinammic Acids</title><p><italic>Caffeic acid phenethyl ester</italic> (CAPE) reverses MDR in breast cancer mouse models due to downregulation of anti-apoptotic and cell proliferation genes, as well as NF-κB transcription factors. Moreover, it decreased <italic>MDR1</italic>-gene expression, so it might be used as an adjuvant to chemotherapeutic agents (paclitaxel) treatment [<xref rid="B267-ijms-21-00401" ref-type="bibr">267</xref>].</p></sec><sec><title>Lignans</title><p><italic>Podophyllotoxin</italic>, a lignan, found in the roots of <italic>Podophyllum peltatum</italic> L. exhibited significant activity against P-gp mediated MDR tumor cell lines [<xref rid="B44-ijms-21-00401" ref-type="bibr">44</xref>]. However, due to its poor solubility, it cannot be used systemically. Nanoparticles composed of poldophyllotoxin and polyethylene glycol with acetylated carboxymethyl cellulose showed beneficial effects in breast and prostate resistant tumor models in mice through enhanced sensitization of tumor cells to chemotherapeutic agents and increased tumor penetration [<xref rid="B44-ijms-21-00401" ref-type="bibr">44</xref>]. Moreover, the delivery of nanoparticles was highly selective to the tumors with minimal uptake in other tissues [<xref rid="B44-ijms-21-00401" ref-type="bibr">44</xref>]. Another lignan, <italic>deoxypodophyllotoxin</italic> from the roots of <italic>Anthriscus sylvestris</italic> exhibited better efficacy to MDR in mouse models for breast cancer than paclitaxel [<xref rid="B45-ijms-21-00401" ref-type="bibr">45</xref>]. According to Lou S. and co-workers a multifunctional nanosystem composed of doxorubicin, paclitaxel and <italic>silybin</italic> controlled drug release, decreased P-gp activity and synergistically inhibited breast tumors growth [<xref rid="B268-ijms-21-00401" ref-type="bibr">268</xref>].</p></sec><sec><title>Other Compounds</title><p>In vivo studies have shown that <italic>curcumin</italic> sensitizes human colorectal cancer to capecitabine in an orthotopic mouse model, through inhibition of NF-κB, decreased expression of genes enconding for proteins involved in proliferation (COX-2), invasion (MMP-2, ICAM-1), metastasis (CXCR4), angiogenesis (VEGF) and anti-apoptotic gene products (Bcl-2, IAP-1 and survivin) [<xref rid="B269-ijms-21-00401" ref-type="bibr">269</xref>]. Other authors reported that curcumin regulates colorectal cancer by inhibiting P-gp in in situ cancerous colon perfusion in a rat model. Inhibition of P-gp enhanced the cytotoxic effects of irinotecan [<xref rid="B270-ijms-21-00401" ref-type="bibr">270</xref>]. According to Howells L. and co-workers curcumin also ameliorates oxaliplatin-induced chemoresistance in HCT-116 xenograft tumors by preventing oxaliplatin-induced upregulation of ALDH1 and decreased activity of excision nucleases, by which DNA lesions are repaired [<xref rid="B271-ijms-21-00401" ref-type="bibr">271</xref>]. Administration of nanoparticles with docetaxel/doxorubicin and curcumin to mice inoculated with prostate cancer cells, overcame MDR to chemotherapeutic agents through enhanced cellular uptake of chemotherapeutic agents and inhibition of MDR1 and MRP [<xref rid="B272-ijms-21-00401" ref-type="bibr">272</xref>,<xref rid="B273-ijms-21-00401" ref-type="bibr">273</xref>]. Moreover, it was shown that curcumin decreases doxorubicin cardiotoxicity [<xref rid="B273-ijms-21-00401" ref-type="bibr">273</xref>]. Besides, curcumin chemosensitizes prostate cancer cells to gemcitabine by downregulation of MDM2 oncogene through PI3K/mTOR/ETS2 pathway [<xref rid="B274-ijms-21-00401" ref-type="bibr">274</xref>]. Cheng et al. investigated the effect of co-administration of curcumin and phospho-sulindac in a mouse xenograft model of human lung cancer. The results were promising, with improved phospho-sulindac pharmacokinetics and higher levels of the chemotherapeutic agent and its metabolites in the xenografts. It was observed that curcumin enhances phospho-sulindac accumulation in cancer tissues through inhibition of P-gp and MRPs [<xref rid="B275-ijms-21-00401" ref-type="bibr">275</xref>]. Cui et al. demonstrated that administration of nanoparticles containing a pH-sensitive pro-drug transferrin-poly(ethylene glycol)-curcumin and doxorubicin exhibited higher cytotoxicity and sensitivity in breast cancer xenograft mouse model compared to the chemotherapeutic agent alone [<xref rid="B276-ijms-21-00401" ref-type="bibr">276</xref>]. </p><p>Few studies have investigated the effect of phenolic compounds for overcoming MDR in humans. According to Mahammedi et al., the combination of curcumin with docetaxel and prednisone showed a high-response rate, good tolerability and acceptability by patients with castration-resistant prostate cancer. It was shown that curcumin reverses docetaxel induced NF-κB activation [<xref rid="B277-ijms-21-00401" ref-type="bibr">277</xref>]. Association between curcumin and docetaxel showed beneficial effects in women with advanced and metastatic breast cancer. Curcumin/docetaxel combination demonstrated significant anti-tumor activity, decreased levels of VEGF and other angiogenic growth factors (TGF-α). Moreover, curcumin improved docetaxel bioavailability and reversed drug resistance through downregulation of P-gp expression [<xref rid="B278-ijms-21-00401" ref-type="bibr">278</xref>]. </p><p>Taken together, these results shown that phenolic compounds overcome MDR in different types of solid cancer (breast, lung, prostate, colorectal) both in vivo and in clinical studies (<xref rid="ijms-21-00401-t003" ref-type="table">Table 3</xref>). However, the data regarding clinical studies with polyphenols and multidrug resistance are very scarce. The mechanisms are generally the same, as previously reported for in vitro studies.</p></sec></sec><sec id="sec3dot2dot3-ijms-21-00401"><title>3.2.3. Bioavailability and Toxicity of the Polyphenols</title><p>Although several studies have shown the beneficial effects of some plant polyphenols in overcoming multi-drug resistance in breast, colorectal, lung, prostate, most of the research was performed using only in vitro (cell lines) and in vivo (animal) models. However, data regarding clinical studies with polyphenols for overcoming chemoresistance are scarce. The extrapolation of the results from pre-clinical studies to humans is difficult and risky, keeping in mind that polyphenols bioavailability is complex and influenced by several factors: (i) chemical structure, (ii) liberation from the food/medicinal plant matrix, (iii) gastro-intestinal absorption, (iv) metabolism by gut microbiota, liver, enterocytes, (v) plasma transport, plasma concentration, (vi) distribution and elimination [<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>,<xref rid="B279-ijms-21-00401" ref-type="bibr">279</xref>,<xref rid="B280-ijms-21-00401" ref-type="bibr">280</xref>,<xref rid="B281-ijms-21-00401" ref-type="bibr">281</xref>]. Polyphenols bioavailability is relatively low, due to low absorption, extensive biotransformation and rapid clearance from the body [<xref rid="B281-ijms-21-00401" ref-type="bibr">281</xref>]. Still, polyphenols metabolites (produced by gut microbiota or liver) reach higher plasma concentrations compared to their parent compounds are considered responsible for polyphenols therapeutic effects. Several polyphenols metabolites such as urolithins (ellagitannins metabolites), enterolactone and enterodiol (lignans metabolites), equol (isoflavones metabolite) have shown a chemopreventive role in breast, prostate or colorectal cancer [<xref rid="B282-ijms-21-00401" ref-type="bibr">282</xref>,<xref rid="B283-ijms-21-00401" ref-type="bibr">283</xref>]. Taken together, clinical studies are imperative in order to demonstrate the beneficial role of polyphenols in overcoming multidrug resistance in various types of cancer.</p><p>In spite of promising results from laboratory experiments, implementation of them into the clinical trials might represent a challenge due to higher concentrations used in those studies. Nevertheless, several clinical studies validated the efficiency of polyphenols against different types of solid tumors [<xref rid="B284-ijms-21-00401" ref-type="bibr">284</xref>,<xref rid="B285-ijms-21-00401" ref-type="bibr">285</xref>,<xref rid="B286-ijms-21-00401" ref-type="bibr">286</xref>]. Administration of regular cytostatic drugs is correlated with severe side effects, such as bone marrow modifications (leucopenia, thrombocytopenia, anemia), nausea, vomiting, alopecia, drug extravasation, hepatotoxicity or heart toxicity [<xref rid="B287-ijms-21-00401" ref-type="bibr">287</xref>,<xref rid="B288-ijms-21-00401" ref-type="bibr">288</xref>]. Conversely, the polyphenols toxicity is greatly reduced and the side effects could be constipation/diarrhea, dry mouth or flatulence [<xref rid="B289-ijms-21-00401" ref-type="bibr">289</xref>]. For example, association of curcumin (0.5, 1, 2 g) for seven days prior to FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) chemotheraphy (two-weekly cycles to a maximum of 12 cycles) in patients with colorectal cancer and liver metastasis, led to several side effects. The most common side effects, which were related to curcumin use (not with FOLFOX) were constipation, dry mouth and flatulence. One patient reported severe diarrhea, attributed to curcumin. Diarrhea was treated when curcumin dosage was changed from 2 g to 1 g and the dosage change did not affect the anticancer effect of curcumin [<xref rid="B289-ijms-21-00401" ref-type="bibr">289</xref>].</p><p>As general considerations, if any of the cytotoxic effects are visible it is recommended to stop the treatment before the irreversible toxic effects occur. In addition, for better toleration of the treatment it is recommended to start the administration when the patient is in good physical condition [<xref rid="B290-ijms-21-00401" ref-type="bibr">290</xref>]. Several general recommendations might be taken in account to reduce toxicity of the polyphenols:</p><p>(i) Combinatorial treatment. Administration of more than one polyphenols or the use of polyphenols as adjuvants in chemotherapy might reduce the concentration of the polyphenols when administrated. For instance, in human colon cancer cells with P-gp overexpression the synergism between DOX and EGCG/curcumin was demonstrated. Thus, lower concentration of DOX and polyphenols are required when co-administrated compared to single drug administration [<xref rid="B291-ijms-21-00401" ref-type="bibr">291</xref>]. Similar synergism was seen in human colorectal cells treated with platinum-based compounds, such as oxaliplatin, cisplatin and EGCG [<xref rid="B292-ijms-21-00401" ref-type="bibr">292</xref>]. </p><p>(ii) Replacement of the natural compound with another one. In a clinical study performed in 49 patients with solid tumors (non-small cell lung cancer, head and neck cancer) the administration of capsules containing a green tea extract (GTE) (standardized in 26.9% total catechins – EGCG – 13.2%; epicatechin 2.2%; epicatechin gallate 3.3%; epigallocatechin 8.3% and 7% caffeine), at increasing dosages up to 8–10 g GTE once daily or 10–13 g distributed over three daily dosages for minimum four weeks to six months, several side effects occurred: nausea, abdominal bloating, headache, insomnia, tremor and palpitations. It was concluded that caffeine was responsible for the above-mentioned side effects. A possible solution to remedy these adverse effects would be the use of Polyphenon E (which is a decaffeinated GTE standardized in 65% EGCG), which was considered safe, when it was given to chronic lymphocytic leukemia patients (400–2000 mg orally twice a day) for one month [<xref rid="B293-ijms-21-00401" ref-type="bibr">293</xref>,<xref rid="B294-ijms-21-00401" ref-type="bibr">294</xref>]. However, Polyphenon E should be administered only with food and not after an overnight fast, due to higher EGCG plasma C<sub>max</sub> (seven-fold higher compared to EGCG administration with food) and high risk of hepatotoxicity [<xref rid="B295-ijms-21-00401" ref-type="bibr">295</xref>]. Another polyphenols, resveratrol has shown kidney toxicity in clinical trials. According to Popat and co-workers the administration of a SRT501, a micronized oral formulation with resveratrol (5 g/day for 20 days in a 21 days cycle, up to 12 cycles followed by bortezomib) in patients with relapsed or refractory multiple myeloma, led to severe side effects (renal failure, nausea, anemia etc.). Renal failure occurred within the first two cycles of SRT501 monotherapy. However, it seems that SRT501 induces kidney failure only in myeloma patients, since the same dose of SRT501 was safe in diabetic patients or stroke-like episodes syndrome [<xref rid="B296-ijms-21-00401" ref-type="bibr">296</xref>]. A solution to remedy renal failure in myeloma patients is the administration of a grape seed extract (rich in resveratrol but also other phenolic compounds. i.e. quercetin, proanthocyanidins), that have strong antioxidant effects and are able to protect the kidneys [<xref rid="B297-ijms-21-00401" ref-type="bibr">297</xref>].</p><p>(iii) Validation the purity of the natural compound. The administration of a green tea extract (rich in catechins, mainly epigalocatechin gallate 11.8–4509 mcg/g extract), in a dosage of 5.9 g over five days to 240 g over 120 days was responsible for hepatic toxicity, mainly acute hepatocellular injury. Still, patients fully recovered with drug cessation [<xref rid="B298-ijms-21-00401" ref-type="bibr">298</xref>,<xref rid="B299-ijms-21-00401" ref-type="bibr">299</xref>]. According to some authors the observed hepatic toxicity of green tea extracts might be the consequence of contamination with pesticides (endosulfan), which is extensively used in green tea plantations [<xref rid="B300-ijms-21-00401" ref-type="bibr">300</xref>].</p><p>(iv) Modes and route of administration. To increase specificity of polyphenols, they can be administrated as nanoparticles which have been coated with antibodies directed against molecular markers from the surface of the tumors [<xref rid="B301-ijms-21-00401" ref-type="bibr">301</xref>,<xref rid="B302-ijms-21-00401" ref-type="bibr">302</xref>]. In addition, local administration of the compound might be used whenever possible [<xref rid="B301-ijms-21-00401" ref-type="bibr">301</xref>].</p></sec></sec></sec><sec sec-type="conclusions" id="sec4-ijms-21-00401"><title>4. Conclusions</title><p>MDR has become the most important obstacle to the success of cancer chemotherapies. It implies several mechanisms, such as increased activity of efflux pumps (MRP 1/2, P-gp, BCRP), inhibition of cell death, cancer stem cells, epigenetic mechanisms, increased DNA repair, modification of drug target, inactivation of anticancer drugs, tumor cell heterogeneity, tumor microenvironment and epithelial to mesenchymal transition. </p><p>The use of natural compounds could overcome MDR through various mechanisms. Several studies have been performed using flavonoid (apigenin, luteolin, quercetin, genistein, epigallocatechin gallate, etc.) and non-flavonoid compounds (lignans, gallic acid, resveratrol, curcumin, etc.). In vitro and in vivo studies have revealed that administration of polyphenols (both from dietary sources and medicinal plants) overcome MDR to chemotherapeutic agents (paclitaxel, 5-fluorouracil, docetaxel, doxorubicin, gefitinib, etc.) in different types of cancer (breast, lung, prostate and colorectal) by downregulation of efflux pumps and anti-apoptotic proteins (survivin, XIAP), downregulation of NF-κB signaling cascade, decreased stem cells progenitor formation, increased cellular uptake of chemotherapeutic agents, epigenetic mechanisms, upregulation of apoptotic factors (DIABLO, APAF1) or modulation of several signaling pathways (Sonic-Hedgehog, EZH2, HER2, ERK, JNK, PI3K/AKT, STAT3, Wnt/β-catenin, etc.) and enzymes (FAS, GSK3, MMP2/MMP9, GST, etc.). However, few clinical studies demonstrated these effects. Therefore, we hope that this review will lead to continuous research regarding the role of phenolic compounds in overcoming multidrug resistance in various types of cancer.</p></sec></body><back><notes><title>Author Contributions</title><p>T.C., M.-M.M., O.C.V., L.-C.M. writing the manuscript, preparing the figures and tables, critical revising of the manuscript; M.-M.M., T.C. conceiving the concept, drafting, editing and critical revising of the manuscript, supervising the manuscript preparation. J.S., C.G. drafting, editing and critical revising of the manuscript, supervising the manuscript preparation. All authors have read and agreed to the published version of the manuscript.</p></notes><notes><title>Funding</title><p>The work was supported by research grants from the National Research, Development and Innovation Office, Hungary (GINOP-2.3.2-15-2016-00050 and GINOP-2.3.3-15-2016-0003). </p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.</p></notes><glossary><title>Abbreviations</title><array orientation="portrait"><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">↑</td><td align="left" valign="middle" rowspan="1" colspan="1">upregulation</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">↓</td><td align="left" valign="middle" rowspan="1" colspan="1">downregulation</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">5-FU </td><td align="left" valign="middle" rowspan="1" colspan="1">5-fluorouracil</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ABC</td><td align="left" valign="middle" rowspan="1" colspan="1">ATP-binding cassette transporter proteins</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ABCB1, ABCG1</td><td align="left" valign="middle" rowspan="1" colspan="1">isoforms of ATP-binding cassette transporter proteins</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ARE</td><td align="left" valign="middle" rowspan="1" colspan="1">antioxidant response element</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ABT-263</td><td align="left" valign="middle" rowspan="1" colspan="1">small molecule that inhibits Bcl-2; 4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}c-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ABT-737</td><td align="left" valign="middle" rowspan="1" colspan="1">small molecule that inhibits Bcl-2; 4-{4-[(4′-Chloro-2-biphenylyl)methyl]-1-piperazinyl}-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)-2-butanyl]amino}-3-nitrophenyl)sulfonyl]benzamide</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">AKT</td><td align="left" valign="middle" rowspan="1" colspan="1">protein kinase B</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ALDH</td><td align="left" valign="middle" rowspan="1" colspan="1">aldehyde dehydrogenase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ALP</td><td align="left" valign="middle" rowspan="1" colspan="1">autophagy lysosomes systems</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">AMPK</td><td align="left" valign="middle" rowspan="1" colspan="1">AMP-activated protein kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">APAF1</td><td align="left" valign="middle" rowspan="1" colspan="1">apoptotic protease activating factor 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">APR-246</td><td align="left" valign="middle" rowspan="1" colspan="1">drug that binds to p53 (restoring p53 function) and depletes glutathione; PRIMA-1, 2-hydroxymethyl-2-methoxymethyl-aza-bicyclo[2.2.2]octan-3-one</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">AR</td><td align="left" valign="middle" rowspan="1" colspan="1">androgen receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ATR</td><td align="left" valign="middle" rowspan="1" colspan="1">serine/threonine protein kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Axl, Tyro3</td><td align="left" valign="middle" rowspan="1" colspan="1">receptors for tyrosine kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BASE</td><td align="left" valign="middle" rowspan="1" colspan="1">base excision repair </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Bax</td><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-2-associated X protein/Bcl-2-like protein 4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-2</td><td align="left" valign="middle" rowspan="1" colspan="1">B cell lymphoma 2 protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-XL</td><td align="left" valign="middle" rowspan="1" colspan="1">B cell lymphoma extra-large protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BCRA1, 2</td><td align="left" valign="middle" rowspan="1" colspan="1">breast cancer susceptible genes</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BCRP</td><td align="left" valign="middle" rowspan="1" colspan="1">breast cancer resistant protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BER</td><td align="left" valign="middle" rowspan="1" colspan="1">base excision repair</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BH</td><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-2 homology domain</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BIM</td><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-2 like protein 11</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BNDQ</td><td align="left" valign="middle" rowspan="1" colspan="1">quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BPIS</td><td align="left" valign="middle" rowspan="1" colspan="1">bound polyphenols of inner shell from foxtail millet bran</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">BRAF</td><td align="left" valign="middle" rowspan="1" colspan="1">serine/threonine-protein kinase B-Raf</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">C</td><td align="left" valign="middle" rowspan="1" colspan="1">catechin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CAB</td><td align="left" valign="middle" rowspan="1" colspan="1">carboplatin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CAPE</td><td align="left" valign="middle" rowspan="1" colspan="1">caffeic acid phenethyl ester</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CAR</td><td align="left" valign="middle" rowspan="1" colspan="1">constitutive androstane receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">caspase-3, 8, 9</td><td align="left" valign="middle" rowspan="1" colspan="1">cysteine aspartic proteases-3, 8, 9</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CBZ</td><td align="left" valign="middle" rowspan="1" colspan="1">cabazitaxel</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CD44, 24, 133</td><td align="left" valign="middle" rowspan="1" colspan="1">cluster of differentiation 44, 24, 133</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CDF</td><td align="left" valign="middle" rowspan="1" colspan="1">difluorinated curcumin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CDK 2,4,6</td><td align="left" valign="middle" rowspan="1" colspan="1">cyclin-dependent kinases 2,4,6</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CDPP</td><td align="left" valign="middle" rowspan="1" colspan="1">cisplatin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CEA</td><td align="left" valign="middle" rowspan="1" colspan="1">carcioembryonic antigen</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">cFLIP</td><td align="left" valign="middle" rowspan="1" colspan="1">regulator of caspase-8 activation; cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CgA</td><td align="left" valign="middle" rowspan="1" colspan="1">chromogranin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Chk1/2</td><td align="left" valign="middle" rowspan="1" colspan="1">Check point kinase 1/2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">cIAP-1,2</td><td align="left" valign="middle" rowspan="1" colspan="1">cellular inhibitor of apoptosis protein 1,2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">COMT</td><td align="left" valign="middle" rowspan="1" colspan="1">catechol-O-methyl transferase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">COX-2</td><td align="left" valign="middle" rowspan="1" colspan="1">ciclo-oxygenase 2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CPT11</td><td align="left" valign="middle" rowspan="1" colspan="1">irinotecan</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CREB-1</td><td align="left" valign="middle" rowspan="1" colspan="1">element binding protein-1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CRPC</td><td align="left" valign="middle" rowspan="1" colspan="1">castration-resistant prostate cancer</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CSC</td><td align="left" valign="middle" rowspan="1" colspan="1">cancer stem cells</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CXCR4</td><td align="left" valign="middle" rowspan="1" colspan="1">CXC chemokine receptor type 4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CYP1A1, CYP1B1, CYP19A1, CYP17A1</td><td align="left" valign="middle" rowspan="1" colspan="1">isoforms of cytochrome 450</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CYP3A4</td><td align="left" valign="middle" rowspan="1" colspan="1">cytochrome P450 3A4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DDR</td><td align="left" valign="middle" rowspan="1" colspan="1">DNA damage response</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DIABLO</td><td align="left" valign="middle" rowspan="1" colspan="1">direct IAP-binding protein with Low pI</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DMBA</td><td align="left" valign="middle" rowspan="1" colspan="1">7,12-dimethylbenz[a] anthracene</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DNA</td><td align="left" valign="middle" rowspan="1" colspan="1">deoxyribonucleic acid </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DOC</td><td align="left" valign="middle" rowspan="1" colspan="1">docetaxel</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DOX</td><td align="left" valign="middle" rowspan="1" colspan="1">doxorubicin (adriamycin)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DPPT</td><td align="left" valign="middle" rowspan="1" colspan="1">deoxypodophyllotoxin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DR4/5</td><td align="left" valign="middle" rowspan="1" colspan="1">pro-apoptotic death receptors</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EC</td><td align="left" valign="middle" rowspan="1" colspan="1">epicatechin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGC</td><td align="left" valign="middle" rowspan="1" colspan="1">epigallocatechin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGCG</td><td align="left" valign="middle" rowspan="1" colspan="1">epigallocatechingallate</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGF</td><td align="left" valign="middle" rowspan="1" colspan="1">epidermal growth factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGFR</td><td align="left" valign="middle" rowspan="1" colspan="1">epithelial growth factor receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGFR(T790M)</td><td align="left" valign="middle" rowspan="1" colspan="1">epithelial growth factor receptor with a mutation that replace threonine by methionine at position 790 </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGR-1</td><td align="left" valign="middle" rowspan="1" colspan="1">early growth response protein 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EMT</td><td align="left" valign="middle" rowspan="1" colspan="1">epithelial-mesenchymal transition</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ENL</td><td align="left" valign="middle" rowspan="1" colspan="1">enterolactone</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ER</td><td align="left" valign="middle" rowspan="1" colspan="1">estrogen receptors</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ERα/ERβ</td><td align="left" valign="middle" rowspan="1" colspan="1">estrogen receptor alpha/estrogen receptor beta</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ERK 1,2</td><td align="left" valign="middle" rowspan="1" colspan="1">extracellular-signal regulated kinase </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ETS2</td><td align="left" valign="middle" rowspan="1" colspan="1">proto-oncogene 2, transcription factor (v-ets, Avian Erythroblastosis Virus E26 Oncogene Homolog 2) </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EZH2</td><td align="left" valign="middle" rowspan="1" colspan="1">enhancer of zeste homolog 2 (histone methyltransferase)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">FASN</td><td align="left" valign="middle" rowspan="1" colspan="1">fatty acid synthase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">FBAP5</td><td align="left" valign="middle" rowspan="1" colspan="1">fatty acid-binding protein 5</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">FGF</td><td align="left" valign="middle" rowspan="1" colspan="1">fibroblast growth factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">FOLFOX</td><td align="left" valign="middle" rowspan="1" colspan="1">5-fluorouracil, oxaliplatin, folinic acid</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GF</td><td align="left" valign="middle" rowspan="1" colspan="1">gefitinib</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GRP78</td><td align="left" valign="middle" rowspan="1" colspan="1">glucose regulated protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GSH</td><td align="left" valign="middle" rowspan="1" colspan="1">reduced glutathione</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GSK3</td><td align="left" valign="middle" rowspan="1" colspan="1">glycogen synthase kinase 3</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GST</td><td align="left" valign="middle" rowspan="1" colspan="1">glutathione-S transferase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GPX</td><td align="left" valign="middle" rowspan="1" colspan="1">glutathione peroxidase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GTE</td><td align="left" valign="middle" rowspan="1" colspan="1">green tea extract</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HER-2, 3</td><td align="left" valign="middle" rowspan="1" colspan="1">human epidermal growth factor 2, 3 </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Her2/neu</td><td align="left" valign="middle" rowspan="1" colspan="1">receptor tyrosine-proteinkinase erbB-2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HGFR/MET</td><td align="left" valign="middle" rowspan="1" colspan="1">hepatocyte growth factor receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HIF-1α</td><td align="left" valign="middle" rowspan="1" colspan="1">hypoxia-inducible factor 1 alpha</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">hMLH1</td><td align="left" valign="middle" rowspan="1" colspan="1">mismatch repair gene of human mutL homolog 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HNK</td><td align="left" valign="middle" rowspan="1" colspan="1">honokiol</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HO-1</td><td align="left" valign="middle" rowspan="1" colspan="1">hemeoxygenase 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HR</td><td align="left" valign="middle" rowspan="1" colspan="1">homologous recombination </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HRas</td><td align="left" valign="middle" rowspan="1" colspan="1">transforming protein p21</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">IAP</td><td align="left" valign="middle" rowspan="1" colspan="1">inhibitors of apoptosis proteins</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ICAM-1</td><td align="left" valign="middle" rowspan="1" colspan="1">intercellular adhesion molecule 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">IGF-1R</td><td align="left" valign="middle" rowspan="1" colspan="1">insulin growth factor receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">IL-6, 8, 17, 18</td><td align="left" valign="middle" rowspan="1" colspan="1">interleukin-6, 8, 17, 18</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">i.p.</td><td align="left" valign="middle" rowspan="1" colspan="1">intraperitoneal administration</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">i.v</td><td align="left" valign="middle" rowspan="1" colspan="1">intravenous administration</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">JNK</td><td align="left" valign="middle" rowspan="1" colspan="1">c-Jun N-terminal kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Keap 1</td><td align="left" valign="middle" rowspan="1" colspan="1">kelch-like ECH-associated protein 1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">KRAS</td><td align="left" valign="middle" rowspan="1" colspan="1">gene identified in Kirsten rat sarcoma</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MAPK</td><td align="left" valign="middle" rowspan="1" colspan="1">mitogen activated protein kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MDM2</td><td align="left" valign="middle" rowspan="1" colspan="1">mouse double minute 2 homolog</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MDR </td><td align="left" valign="middle" rowspan="1" colspan="1">multidrug resistance</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Meriva</td><td align="left" valign="middle" rowspan="1" colspan="1">turmeric/phospholipid formulation </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MET</td><td align="left" valign="middle" rowspan="1" colspan="1">tyrosine-proteinkinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MLH1,2</td><td align="left" valign="middle" rowspan="1" colspan="1">human mutL homolog 1,2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MMP</td><td align="left" valign="middle" rowspan="1" colspan="1">mitochondrial membrane potential</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MMP-2,9</td><td align="left" valign="middle" rowspan="1" colspan="1">metalloproteinases 2,9</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MMR</td><td align="left" valign="middle" rowspan="1" colspan="1">mismatch repair</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MRP1/2</td><td align="left" valign="middle" rowspan="1" colspan="1">multidrug resistance associated protein 1/2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">mRNA</td><td align="left" valign="middle" rowspan="1" colspan="1">messenger RNA</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">miRNA</td><td align="left" valign="middle" rowspan="1" colspan="1">microRNA</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">miR-16, 17, 21, 200c, 17-5p, 892c</td><td align="left" valign="middle" rowspan="1" colspan="1">microRNA-16, 17, 21, 200c, 17-5p, 892c </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MSH 1/2</td><td align="left" valign="middle" rowspan="1" colspan="1">DNA mismatch repair protein 1/2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">mTOR</td><td align="left" valign="middle" rowspan="1" colspan="1">mammalian target of rapamycin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NAD(P)H</td><td align="left" valign="middle" rowspan="1" colspan="1">reduced nicotinamide adenine dinucleotide phosphate</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NER</td><td align="left" valign="middle" rowspan="1" colspan="1">nucleotide excision repair</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NF-κB</td><td align="left" valign="middle" rowspan="1" colspan="1">nuclear factor kappa-light-chain-enhancer of activated B cells</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NGF</td><td align="left" valign="middle" rowspan="1" colspan="1">nerve growth factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NHEJ</td><td align="left" valign="middle" rowspan="1" colspan="1">non-homologous end-joining</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NOX</td><td align="left" valign="middle" rowspan="1" colspan="1">NADPH oxidases</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NPs</td><td align="left" valign="middle" rowspan="1" colspan="1">nanoparticles</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Nrf2</td><td align="left" valign="middle" rowspan="1" colspan="1">erythroid 2-related factor 2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NSCLC</td><td align="left" valign="middle" rowspan="1" colspan="1">non-small cell lung cancer</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">NSE</td><td align="left" valign="middle" rowspan="1" colspan="1">neurospecific enolase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">OX</td><td align="left" valign="middle" rowspan="1" colspan="1">oxaliplatin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">p53</td><td align="left" valign="middle" rowspan="1" colspan="1">tumor suppressor protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">P-gp (MDR1)</td><td align="left" valign="middle" rowspan="1" colspan="1">P-glycoprotein (multidrug resistance protein 1)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PI3K/AKT</td><td align="left" valign="middle" rowspan="1" colspan="1">phosphoinositide 3-kinase/protein kinase B</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PKC </td><td align="left" valign="middle" rowspan="1" colspan="1">proteinkinase C</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">p.o.</td><td align="left" valign="middle" rowspan="1" colspan="1">oral administration</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PPARβ/δ</td><td align="left" valign="middle" rowspan="1" colspan="1">peroxisome proliferator-activated receptor β/δ</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PPT</td><td align="left" valign="middle" rowspan="1" colspan="1">podophyllotoxin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PS </td><td align="left" valign="middle" rowspan="1" colspan="1">phospho-sulindac </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PSA</td><td align="left" valign="middle" rowspan="1" colspan="1">prostate serum antigen</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PTEN</td><td align="left" valign="middle" rowspan="1" colspan="1">phosphatase and tensin homolog</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PTX</td><td align="left" valign="middle" rowspan="1" colspan="1">paclitaxel</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PXR</td><td align="left" valign="middle" rowspan="1" colspan="1">pregnane X receptor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">RARs</td><td align="left" valign="middle" rowspan="1" colspan="1">retinoic acid receptors</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">RES</td><td align="left" valign="middle" rowspan="1" colspan="1">resveratrol</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ROS</td><td align="left" valign="middle" rowspan="1" colspan="1">reactive oxygen species</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SCC</td><td align="left" valign="middle" rowspan="1" colspan="1">squamous cell carcinoma</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SChA</td><td align="left" valign="middle" rowspan="1" colspan="1">schizandrin A</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SCLC</td><td align="left" valign="middle" rowspan="1" colspan="1">small cell lung cancer</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SECO</td><td align="left" valign="middle" rowspan="1" colspan="1">secoisolariciresinol</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Smac</td><td align="left" valign="middle" rowspan="1" colspan="1">second mitochondria-derived activator of caspase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SOD</td><td align="left" valign="middle" rowspan="1" colspan="1">superoxide-dismutase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Src</td><td align="left" valign="middle" rowspan="1" colspan="1">proto-oncogene tyrosine-protein kinase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SRT501</td><td align="left" valign="middle" rowspan="1" colspan="1">small molecule, a form of resveratrol designed to target sirtuin 1 protein </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="left" valign="middle" rowspan="1" colspan="1">signal transducer and activator of transcription 3</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">T-box 3</td><td align="left" valign="middle" rowspan="1" colspan="1">T-box transcription factor 3</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Tf-PEG-CUR</td><td align="left" valign="middle" rowspan="1" colspan="1">transferrin-poly(ethylene glycol)-curcumin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TGF-β</td><td align="left" valign="middle" rowspan="1" colspan="1">transforming growth factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TKI</td><td align="left" valign="middle" rowspan="1" colspan="1">tyrosine kinase inhibitors</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TME</td><td align="left" valign="middle" rowspan="1" colspan="1">tumor microenvironment</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TP53</td><td align="left" valign="middle" rowspan="1" colspan="1">gene coding tumor suppressor protein p53</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TRAIL</td><td align="left" valign="middle" rowspan="1" colspan="1">TNF-related apoptosis-inducing ligand</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">UGT</td><td align="left" valign="middle" rowspan="1" colspan="1">uridine diphospho-glucuronosyltransferase</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">VCR</td><td align="left" valign="middle" rowspan="1" colspan="1">vincristine</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">VEGF</td><td align="left" valign="middle" rowspan="1" colspan="1">vascular endothelial growth factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">VEGFR2</td><td align="left" valign="middle" rowspan="1" colspan="1">vascular endothelial growth factor receptor 2 </td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Wnt/β-catenin</td><td align="left" valign="middle" rowspan="1" colspan="1">wingless-type MMTV integration site family member (MMTV, mouse mammary tumor virus)/beta-catenin signaling pathway</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">xCT</td><td align="left" valign="middle" rowspan="1" colspan="1">glutamate cysteine antiporter</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">XIAP</td><td align="left" valign="middle" rowspan="1" colspan="1">X-linked inhibitor of apoptosis 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thin;border-bottom:solid thin" rowspan="1" colspan="1">Chemical Structure</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Representative Compounds</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Sources</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td colspan="5" align="center" valign="middle" rowspan="1"><bold>Flavonoid Compounds</bold></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Flavones</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i001.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">apigenin<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–H, R<sub>3</sub>–H)<break></break>luteolin<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–H)<break></break>wogonin<break></break>(R<sub>1</sub>–H, R<sub>2</sub>–H, R<sub>3</sub>–OCH<sub>3</sub>)</td><td rowspan="2" align="center" valign="middle" colspan="1">oranges, lemons, apricots, apples, black currants, bananas, potatoes, spinach, onions, lettuce, parsley, celery, beans, tomatoes, roots of <italic>Scutellaria baicalensis</italic> Georgi</td><td rowspan="2" align="center" valign="middle" colspan="1">[<xref rid="B37-ijms-21-00401" ref-type="bibr">37</xref>,<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>,<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>,<xref rid="B41-ijms-21-00401" ref-type="bibr">41</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Flavonols</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i002.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">quercetin<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–H, R<sub>4</sub>–OH, R<sub>5</sub>–OH)<break></break>fisetin<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–H, R<sub>3</sub>–OH, R<sub>4</sub>–OH, R<sub>5</sub>–H)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Flavanones</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i003.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">naringenin<break></break>(R<sub>1</sub>–H, R<sub>2</sub>–OH)<break></break>hesperitin<break></break>(R<sub>1</sub>–OCH<sub>3</sub>, R<sub>2</sub>–OH)</td><td align="center" valign="middle" rowspan="1" colspan="1">oranges, grapefruits, lemons</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Flavan-3-ols</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i004.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">catechin (C), epicatechin (EC)<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–H, R<sub>4</sub>–H)<break></break>epigallocatechin (EGC)<break></break>(R<sub>1</sub>– OH, R<sub>2</sub>–OH, R<sub>3</sub>–OH, R<sub>4</sub>–H)<break></break>epigallocatechingallate (EGCG)<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–OH,<break></break>R<sub>4</sub>—<inline-graphic xlink:href="ijms-21-00401-i005.jpg"></inline-graphic>)</td><td align="center" valign="middle" rowspan="1" colspan="1">green/black tea, grapes, cherries, apricots, peaches</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>,<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Isoflavones</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i006.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">genistein<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–OH)<break></break>daidzein<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–H, R<sub>3</sub>–OH)</td><td align="center" valign="middle" rowspan="1" colspan="1">soy flour, soy paste (natto, cheonggukang), soy bean (roasted)</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B38-ijms-21-00401" ref-type="bibr">38</xref>]</td></tr><tr><td colspan="5" align="center" valign="middle" rowspan="1"><bold>Non-Flavonoid Compounds</bold></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Hydroxy-benzoic acids</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i007.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">gallic acid<break></break>(R<sub>1</sub>–OH, R<sub>2</sub>–OH, R<sub>3</sub>–OH, R<sub>4</sub>–OH)</td><td align="center" valign="middle" rowspan="1" colspan="1">blackcurrants, strawberries, raspberries, kiwi, cherry, plums, spinach, broccoli</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>,<xref rid="B42-ijms-21-00401" ref-type="bibr">42</xref>] </td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Hydroxy-cinnamic acids</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i008.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">caffeic acid<break></break>(R<sub>1</sub>–H, R<sub>2</sub>–OH, R<sub>3</sub>–OH)<break></break>ferulic acid<break></break>(R<sub>1</sub>–H, R<sub>2</sub>–OH, R<sub>3</sub>–OCH<sub>3</sub>)<break></break>cinnamic acid<break></break>(R<sub>1</sub>–H, R<sub>2</sub>–H, R<sub>3</sub>–H)</td><td align="center" valign="middle" rowspan="1" colspan="1">plums, apples, eggplants, potatoes, wheat, rice, oat, kiwi</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i009.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">caffeic acid phenethyl ester (CAPE)</td><td align="center" valign="middle" rowspan="1" colspan="1">artichoke, oregano, thyme, basil, coffee, mushrooms</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]</td></tr><tr><td rowspan="5" align="center" valign="middle" colspan="1"><bold>Lignans</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i010.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">honokiol</td><td align="center" valign="middle" rowspan="1" colspan="1">bark, root, seeds, leaves of <italic>Magnolia</italic> sp.</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B43-ijms-21-00401" ref-type="bibr">43</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i011.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">podophyllotoxin<break></break>(R–OH)<break></break>deoxypodophyllotoxin<break></break>(R–H)</td><td align="center" valign="middle" rowspan="1" colspan="1">rhizome of American mayapple (<italic>Podophyllum peltatum</italic> L.)<break></break>roots of <italic>Anthriscus sylvestris</italic> L. (Hoffm.)</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B44-ijms-21-00401" ref-type="bibr">44</xref>,<xref rid="B45-ijms-21-00401" ref-type="bibr">45</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i012.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">silybin (silibinin)</td><td align="center" valign="middle" rowspan="1" colspan="1">fruits of milk twistle (<italic>Silybum marianum</italic> L.) Gaerth</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B46-ijms-21-00401" ref-type="bibr">46</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i013.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">secoisolariciresinol</td><td align="center" valign="middle" rowspan="1" colspan="1">flaxseeds</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B47-ijms-21-00401" ref-type="bibr">47</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i014.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">schizandrin A</td><td align="center" valign="middle" rowspan="1" colspan="1">fruits of <italic>Schisandra chinensis</italic></td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B48-ijms-21-00401" ref-type="bibr">48</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" colspan="1"><bold>Ellagitannins</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i015.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">ellagic acid</td><td align="center" valign="middle" rowspan="1" colspan="1">raspberries, strawberries,<break></break>pomegranate black currants, blackberries</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B49-ijms-21-00401" ref-type="bibr">49</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i016.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">sanguiin-H6</td><td align="center" valign="middle" rowspan="1" colspan="1">raspberries</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B49-ijms-21-00401" ref-type="bibr">49</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>Stilbenes</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i017.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">resveratrol</td><td align="center" valign="middle" rowspan="1" colspan="1">grapes, mulberries</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B40-ijms-21-00401" ref-type="bibr">40</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>Other Compounds</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i018.jpg"></inline-graphic></td><td align="center" valign="middle" rowspan="1" colspan="1">curcumin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>Curcuma</italic> roots</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B50-ijms-21-00401" ref-type="bibr">50</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-00401-i019.jpg"></inline-graphic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">gingerol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">fresh/dried<break></break>ginger<break></break>rhizomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B51-ijms-21-00401" ref-type="bibr">51</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="ijms-21-00401-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-21-00401-t002_Table 2</object-id><label>Table 2</label><caption><p>Summary of in vitro experiments.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type of Cancer</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Line</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment/Duration</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanisms of Overcoming MDR</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Flavonoid Compounds</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Apigenin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD44<sup>+</sup> PC3 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15 μM apigenin +<break></break>7.5 μM CDPP,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Bcl-2,<break></break>↓ sharpin,<break></break>↓ survivin,<break></break>↑ caspase 8,<break></break>↑ APAF-1, ↑ p53 mRNA, ↓ NF-κB, ↑ p21, ↓ CDK-2,<break></break>↓ CDK-4,<break></break>↓ CDK-6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B188-ijms-21-00401" ref-type="bibr">188</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wogonin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549 cell line</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10 μM wagonin + TRAIL (5–20 ng/mL), 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↓ cFLIP<sub>L</sub>, ↓ XIAP, ↓ cIAP-1, ↓ IAP-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B41-ijms-21-00401" ref-type="bibr">41</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Luteolin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ABCG2 expressing MCF-7 cells mitoxantrone resistant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12.5–100 μM luteolin + 1 μM mitoxantrone, 4 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ ROS, ↑ DNA damage, ↓ NF-κB<break></break>↓ cIAP-1,<break></break>↓ survivin,<break></break>↓ XIAP<break></break>↑ ATR-CHk2-p53</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B189-ijms-21-00401" ref-type="bibr">189</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB 231 cells DOX resistant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5–20 μM luteolin +<break></break>0.08–20 mM DOX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Nrf2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B191-ijms-21-00401" ref-type="bibr">191</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pre-treatment<break></break>(24 h) with 5 μM luteolin before DOX<break></break>(0–3 μg/mL),<break></break>OX (0–100 μM), bleomycin<break></break>(0–100 μM), 48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Nrf2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B190-ijms-21-00401" ref-type="bibr">190</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Quercetin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOX resistant MCF-7 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.5 μg/mL DOX, 0.5 μg/mL PTX,<break></break>0.5 μg/mL VCR + 0.5. μg/ml quercetin - 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, ↓ YB-1 nuclear protein translocation,<break></break>↓ BCSCs phenotype CD44<sup>+</sup>/CD24<sup>−</sup>/<sup>low</sup>,<break></break>↑ apoptosis, cell cycle arrest</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B192-ijms-21-00401" ref-type="bibr">192</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VCR resistant Caco-2 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.5–200 μM quercetin, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B193-ijms-21-00401" ref-type="bibr">193</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20 μM cimetidine +<break></break>100 μM quercetin,<break></break>4 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B194-ijms-21-00401" ref-type="bibr">194</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fisetin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OX-resistant LoVo cells<break></break>CPT11-resistant LoVo cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0 μM, 40 μM,<break></break>80 μM fisetin,<break></break>24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↑ cytochrome C release, ↓ IGF-1R and AKT phosphorylation levels</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B196-ijms-21-00401" ref-type="bibr">196</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Naringenin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Daunomycin resistant MCF-7 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9 × 10<sup>−8</sup> M–<break></break>7.2 × 10<sup>−5</sup> M daunomycin +<break></break>50 μM naringenin, 72 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B195-ijms-21-00401" ref-type="bibr">195</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Hesperitin glycoside<break></break>(hesperidin)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7 DOX resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.5–3.5 μM/L hesperidin +<break></break>35–233 nM/L DOX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B197-ijms-21-00401" ref-type="bibr">197</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Coco-2 cells overexpressing<break></break>P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">32 μM hesperidin, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B198-ijms-21-00401" ref-type="bibr">198</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Catechin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MDB-231 CDPP resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5, 10, 20, 40 μM C + 10 μM CDPP, 6 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ ATR-Chk1 pathway</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B199-ijms-21-00401" ref-type="bibr">199</xref>]</td></tr><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">EGCG</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tamoxifen-resistant MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nrf2-RNA transfection, 48 h + 50/100 μM EGCG, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Nrf2 signaling pathway</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B202-ijms-21-00401" ref-type="bibr">202</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT-116<break></break>DLD1 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 μM EGCG +<break></break>0–30 μM 5-FU,<break></break>24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ GRP78/<break></break>NF-κB/miR-155-5p/MDR1 pathway</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B203-ijms-21-00401" ref-type="bibr">203</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PC3, LAPC4 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">40 μM EGCG +<break></break>5 μM quercetin +<break></break>5 nM DOC,<break></break>24/48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD44<sup>+</sup>/CD24<sup>−</sup> cells, ↓ MRP1,<break></break>↓ PI3K/AKT/<break></break>STAT3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B204-ijms-21-00401" ref-type="bibr">204</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549/H460<break></break>CDPP resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">80 μM EGCG + 0–30 μM CDPP, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Axl, Tyro3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B205-ijms-21-00401" ref-type="bibr">205</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Genistein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7 DOX resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–120 μmol/L genistein +<break></break>0.7–70 μM DOX, 48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ HER 2/neu,<break></break>↑ apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B206-ijms-21-00401" ref-type="bibr">206</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate<break></break>Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PC-3 cells<break></break>H460 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">pre-treatment with<break></break>15–30 μmol/L genistein, 24 h<break></break>1–2 nM DOC/100 nM/L cisplatin,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↓ NF-κB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B207-ijms-21-00401" ref-type="bibr">207</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Daidzein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7/<break></break>MDA-MB 231 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">pre-treatment with 10 μM daidzein,<break></break>24 h before administration of 0–10 mM DOX/<break></break>mitoxantrone</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MRP1/2,↓BCRP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B208-ijms-21-00401" ref-type="bibr">208</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">NON-FLAVONOID COMPOUNDS</td></tr><tr><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Resveratrol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 µM RES +<break></break>20 nM rapamycin, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ mTOR, ↓ AKT, ↑ autophagy</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B209-ijms-21-00401" ref-type="bibr">209</xref>] </td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOX resistant MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4–16 µM RES + 4–64 µM DOX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B210-ijms-21-00401" ref-type="bibr">210</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SK-BR-3, MCF7, MDA-MB-231, T47D cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15 µM RES +<break></break>1 nM DOC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ HER2-AKT axis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B214-ijms-21-00401" ref-type="bibr">214</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCI-H460 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–20 µg/mL RES +<break></break>0–10 µg/mL PTX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, MRP2, BCRP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B211-ijms-21-00401" ref-type="bibr">211</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GF resistant NSCLC- PC9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1–20 µM GF +<break></break>5–160 µM RES</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↑ senescence</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B213-ijms-21-00401" ref-type="bibr">213</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT 116, HT-29 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.3 µM DOX +<break></break>100 µM RES</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, ↑ Bax, cell cycle arrest</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B212-ijms-21-00401" ref-type="bibr">212</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Honokiol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7/DOX, MDA-MB-231</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 µL polymeric micelles with<break></break>1 mg PTX +<break></break>0.5 mg/L HNK, 24/36 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, ↑ plasma fluidity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B43-ijms-21-00401" ref-type="bibr">43</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT-116 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–50 μM HNK +<break></break>0–5 Gy γ-radiation, 24/48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↓ cyclin A1, D1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B215-ijms-21-00401" ref-type="bibr">215</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Secoisolarici<break></break>resinol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB-231, SKBR3 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">25–50 µM SECO, 25–50 µM ENL,<break></break>20 nM DOX,<break></break>1 nM DOC,<break></break>1000 nM CAB, 72 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ FAS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B47-ijms-21-00401" ref-type="bibr">47</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Schizandrin A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5-FU resistant HCT116, SW-480</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–8 µM 5-FU +<break></break>0–40 µM SchA,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ mir-195</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B48-ijms-21-00401" ref-type="bibr">48</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Silybin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB 435 DOX resistant cell line<break></break>MCF-7 PTX resistant cell line</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200–600 μM silybin +<break></break>0–35 μg/mL DOX/250 nM PTX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ STAT3, ERK, AKT</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B46-ijms-21-00401" ref-type="bibr">46</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Gallic acid </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SCLC H446 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2–12 µg/mL<break></break>gallic acid +<break></break>3.12–50 µg/mL CDPP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis, MMP disruption<break></break>↑ Bax, ↑ APAF1, ↑ p53,<break></break>↑ DIABLO,<break></break>↓ XIAP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B219-ijms-21-00401" ref-type="bibr">219</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7/DOX cells<break></break>MCF-7/DOX<sub>500</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30–120 µM<break></break>gallic acid +<break></break>5–20 µM EGCG, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MMP-2/<break></break>MMP-9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B220-ijms-21-00401" ref-type="bibr">220</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCC827, H1650, H1975, H358, H1666 cells TKI resistant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20–100 µM gallic acid +<break></break>0.1–5 µM GF, 5 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Src-STAT3,<break></break>↑ apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B221-ijms-21-00401" ref-type="bibr">221</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cinnamic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chemoresistant H1299-derived stem-like cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1–32 mM<break></break>cinnamic acid;<break></break>4 mM<break></break>cinnamic acid +<break></break>4–32 µM PTX/<break></break>4–32 μg/mL CDPP, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ differentiation into CD33 negative cells;<break></break>↓chemoresistance to cisplatin and PTX</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B227-ijms-21-00401" ref-type="bibr">227</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caffeic acid/<break></break>ferulic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT-8 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pre-treatment - 0.5–1 mg/mL BPIS (12 h) before 1000–6000 µM 5-FU,<break></break>50–400 µM OX,<break></break>25–125 µM VCR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, MRP1, BCRP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B222-ijms-21-00401" ref-type="bibr">222</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Caffeic acid phenethyl ester (CAPE)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB-231 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10–40 µM CAPE, 4.5 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD44 cells,<break></break>↓ progenitor formation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B223-ijms-21-00401" ref-type="bibr">223</xref>] </td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB-231, T47D cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pretreatment with<break></break>1 µM CAPE<break></break>(72 h) before irradiation<break></break>(2–8 Gy)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ DNA damage</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B224-ijms-21-00401" ref-type="bibr">224</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10, 50 µM CAPE<break></break>10 µM DOX, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ chemosensitivity to DOX,<break></break>↓ claudin -2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B226-ijms-21-00401" ref-type="bibr">226</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ellagic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SW480, Colo 320DM,<break></break>HT-29 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5–25 µM 5-FU +<break></break>2–25 µM<break></break>ellagic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ Bax/Bcl-2 ratio, ↑ caspase-3<break></break>↓ mitochondrial potential</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B217-ijms-21-00401" ref-type="bibr">217</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sanguiin-H6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOX resistant MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–313 µM sanguiin-H6,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ ABC transporters</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B218-ijms-21-00401" ref-type="bibr">218</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Non-Flavonoid Compounds</bold></td></tr><tr><td rowspan="10" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Curcumin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OX-resistant HTOXAR3, LoVOXAR3 DLDOXAR3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5–10 μM curcumin +<break></break>10–30 μM OX, –<break></break>24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓NF-κB signaling cascade,<break></break>↓ CXCL8, CXCL1, CXCL2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B230-ijms-21-00401" ref-type="bibr">230</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VCR resistant HCT8/VCR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6.25–100 μM curcumin +<break></break>0.5 μg/l VCR,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B228-ijms-21-00401" ref-type="bibr">228</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5-FU and OX resistant HCT-116, SW-620</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 nM CDF</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ miR-21</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B232-ijms-21-00401" ref-type="bibr">232</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549-CDPP resistant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20 μg/mL CDDP +<break></break>10 μM curcumin, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ autophagy,<break></break>↓ Nrf2 activation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B233-ijms-21-00401" ref-type="bibr">233</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A549/DOX cells,<break></break>P-gp overexpressing DOX resistant overexpressing</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nanomicelles with<break></break>1–30 μg/mL DOX +<break></break>curcumin<break></break>(1.6 times concentration of DOX), 72 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ sensitivity to DOX, ↑ cellular uptake</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B234-ijms-21-00401" ref-type="bibr">234</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CDPP resistant A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5–20 μM curcumin +<break></break>1.5 μg/mL CDPP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↓ HIF-1α</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B235-ijms-21-00401" ref-type="bibr">235</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tamoxifen resistant MCF-7/LCC2,<break></break>MCF-7/LCC9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30 μM curcumin, 24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ mTOR, ↓ EZH2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B236-ijms-21-00401" ref-type="bibr">236</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7,<break></break>MDA-MB-231,<break></break>SK-BR-3 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10 μM curcumin<break></break>6 h before 5-FU<break></break>(10 μM)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ NF-κB signaling cascade</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B231-ijms-21-00401" ref-type="bibr">231</xref>] </td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOX resistant MCF-7 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–20 mM curcumin +<break></break>0–4 mΜ EGCG</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Bcl-2,<break></break>↓ survivin,<break></break>↑ caspase 7, 9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B238-ijms-21-00401" ref-type="bibr">238</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA-MB-231, MDA-MB-468,<break></break>SK-BR-3, MCF-7 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30 μM curcumin and/or<break></break>1 μM trans retinoic acid,<break></break>48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ sensitivity to retinoic acid<break></break>↓ FBAP5, PPARβ/δ</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B237-ijms-21-00401" ref-type="bibr">237</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Gingerol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOC resistant PC3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 µM<break></break>6-gingerol +<break></break>100 µM<break></break>10-gingerol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MRP1, ↓GST</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B51-ijms-21-00401" ref-type="bibr">51</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">cyclophosphamide, 5-5-FU, DOX resistant MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50–250 µM<break></break>6-gingerol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Wnt/β-catenin, ↓ GSK3 </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B239-ijms-21-00401" ref-type="bibr">239</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Legend: 5-FU—5-fluorouracil, CDF—difluorinated curcumin, ↓—downregulation, ↑—upregulation, m-TOR—mammalian target of rapamycin, EZH2—enhancer of zeste homolog 2, CDPP—cisplatin, Nrf2—erythroid 2-related factor 2, DOX—doxorubicin (adriamycin), EGCG—epigallocatechingallate, Bcl-2—Bcl-lymphoma 2, Bax—Bcl-2-like protein 4, MRP1/2—multidrugresistance associated protein 1/2, GST—gluthatione-S transferase, GSK3—glycogen synthase kinase 3, AKT—protein kinase B, RES—resveratrol, P-gp—P-glycoprotein (MDR1), PTX—paclitaxel, BCRP—breast cancer resistant protein, GF—gefitinib, HER-2—human epidermal growth factor 2, HNK—honokiol, MMP—mitochondrial membrane potential, APAF1—apoptotic protease activating factor 1, DIABLO—second mitochondria-derived activator of caspases, XIAP—inhibitor of apoptosis protein 3, MMP-2/MMP-9—metalloproteinase, TKI—tyrosine kinase inhibitors (gefitinib), SChA—schizandrin A, SECO—secoisolariciresinol, ENL—enterolactone, DOC—docetaxel, CAB—carboplatin, FAS—fatty acid synthase, CSC—cancer stem cells, OX—oxalipaltin, VCR—vincristine, FBAP5—fatty acid-binding protein 5, PPARβ/δ—peroxisome proliferator-activated receptor β/δ, HIF-1α—hypoxia-inducible factor 1 alpha, NSCLC—non-small cell lung cancer, EMT—epithelial to mesenchymal transition, CREB -1—element binding protein-1, STAT3—signal transducer and activator of transcription 3, ERK—extracellular-signal regulated kinase, EGFR—epidermal growth factor receptor, CDK—cyclin-dependent kinase, IAP—inhibitors of apoptosis proteins, cFLIPL—regulator of caspase-8 activation, ATR—protein kinase, p-53—cellular tumor antigen, Chk1/2—Check point kinase 1/2, ROS—reactive oxygen species, YB-1—Y-box binding protein, CPT11—irinotecan, PI3K/AKT—phosphoinositide 3-kinase/protein kinase B, JNK—c-Jun N-terminal kinase, GRP78—glucose regulated protein, Axl, Tyro3—receptors for tyrosine kinase, TRAIL—TNF-related apoptosis-inducing ligand, NA—not applicable, C—catechin, Nf-kb—nuclear factor kappa-light-chain-enhancer of activated B cells, IGF-1R—insulin growth factor, EGCG—epigallocatechingallate, Her2/neu—receptor tyrosine-proteinkinase erB-2, XIAP—inhibitor of apoptosis protein 3, Src- proto-oncogene tyrosine-protein kinase, BPIS—bound polyphenols of inner shell from foxtail millet bran, CAPE—caffeic acid phenethyl ester, ABC—ATP-binding cassette transporter proteins.</p></fn></table-wrap-foot></table-wrap><table-wrap id="ijms-21-00401-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-21-00401-t003_Table 3</object-id><label>Table 3</label><caption><p>Summary of in vivo and clinical experiments.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type of Cancer</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Model System</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Doses<break></break>and Duration of Administration</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanisms of Overcoming MDR</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Flavonoid Compounds</bold></td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Quercetin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Sprague–Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5, 7.5, 10 mg/kg quercetin p.o. +<break></break>10 mg/kg tamoxifen p.o.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp, ↓ MRP2, ↓ BCPR, ↓ CYP3A4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B257-ijms-21-00401" ref-type="bibr">257</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c nude mouse model for MCF-7 DOX resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 mg/kg BNDQ i.v.<break></break>20 days, every three days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B258-ijms-21-00401" ref-type="bibr">258</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wogonin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model for A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 mg/kg TRAIL i.p. +<break></break>100 mg/kg wogonin i.p.<break></break>3 times/week, 28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ ROS, ↑ apoptosis,<break></break>↓ cFLIP<sub>L</sub>, ↓ XIAP,<break></break>↓ cIAP-1, ↓ IAP-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B41-ijms-21-00401" ref-type="bibr">41</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fisetin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft nude mouse model for Lovo OX/irinotecan resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">400 mg/kg/day fisetin and<break></break>800 mg/kg/day fisetin p.o., 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↑ cytochrome C release,<break></break>↓ IGF1R/AKT,<break></break>↓ tumor volumes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B196-ijms-21-00401" ref-type="bibr">196</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Luteolin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c nude mouse model for NCI-H1975 erlotinib resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10/30 mg/kg/day luteolin i.p. +<break></break>100 mg/kg/day erlotinib i.p. +<break></break>2 mg/kg/day CDPP i.p.,<break></break>15 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ tumor volumes,<break></break>↓ EGFR,<break></break>↓ PI3K/AKT mTOR<break></break>↑ apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B259-ijms-21-00401" ref-type="bibr">259</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Genistein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse models for<break></break>A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 mg/kg CDPP i.p., day one + 800 μg/kg genistein p.o.,<break></break>5 days,<break></break>5 mg/kg CDPP i.p.<break></break>day one + 500 μg/kg genistein p.o.,<break></break>4 days, every 7 days for 21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ tumor volumes,<break></break>↓ PI3/AKT</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B262-ijms-21-00401" ref-type="bibr">262</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse models<break></break>for H1975 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 mg/kg GF p.o. + 100 mg/kg genistein p.o.,<break></break>5 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ EGFR,<break></break>↓ mTOR,<break></break>↑ caspase -3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B263-ijms-21-00401" ref-type="bibr">263</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">EGCG</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse models for breast 4T1 cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGCG 30 mg/kg/day i.v. +<break></break>PTX 10 mg/kg i.v.,<break></break>every two days, 24 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ apoptosis,<break></break>↓ GRP78,<break></break>↓ JNK phosphorylation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B260-ijms-21-00401" ref-type="bibr">260</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Sprague–Dawley rats treated with DMBA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 mg/kg PTX i.p. +<break></break>10 mg/kg EGCG i.p.,<break></break>twice/week, 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CD44 cells,<break></break>↓ VEGF,<break></break>↓ MMP-2,<break></break>↑ caspase-3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B261-ijms-21-00401" ref-type="bibr">261</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Non-Flavonoid Compounds</bold></td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Resveratrol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse model<break></break>for MCF-7/Adr resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liposomes with<break></break>8 mg/kg PTX +<break></break>20 mg/kg RES i.v.,<break></break>every two days, 14 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ cellular uptake of PTX,<break></break>↓ P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B264-ijms-21-00401" ref-type="bibr">264</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c nude mouse model<break></break>for HCT-116 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg RES +<break></break>10 mg/kg OX i.v. every day, 14 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ miR-34c</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B265-ijms-21-00401" ref-type="bibr">265</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse model (females)<break></break>for SPC-A-1/CDDP cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 g/kg/day RES p.o.,<break></break>3 g/kg/day RES p.o., 28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ survivin,<break></break>↑ apoptosis (caspase 3)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B266-ijms-21-00401" ref-type="bibr">266</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caffeic acid phenethyl exter (CAPE)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft Ncr-<italic>nu/nu</italic> mouse models for<break></break>MCF-7, MDA-MB-213 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10, 50, 250 nmol/mouse CAPE p.o.,<break></break>every day, 60 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ NF-κB,<break></break>↓ EGFR, IFGR,<break></break>↓ MDR1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B267-ijms-21-00401" ref-type="bibr">267</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Podophyllotoxin (PPT)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast and<break></break>prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c and NOD-SCID mouse models EMT6/AR1 (breast), PC3 (prostate) cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12 mg/kg DOC i.v.,<break></break>every 4 days, 8 days;<break></break>5 mg/kg CBZ i.v.,<break></break>every 4 days, 8 days;<break></break>180 mg/kg PPT NPs i.v.<break></break>every 4 days, 8 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp,<break></break>↑ cellular uptake of chemotherapeutic agents</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B44-ijms-21-00401" ref-type="bibr">44</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Deoxypodophyllotoxin<break></break>(DPPT)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model MCF-7 DOX resistant cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.25 mg/kg DPPT i.v. +<break></break>12.5 mg/kg PTX i.v.<break></break>every 3 days, 10 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">efflux transport</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B45-ijms-21-00401" ref-type="bibr">45</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Silybin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model (females)<break></break>for MDA-MB-231 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.5 mg/kg nanosystems −<break></break>75 μg/mg DOX +<break></break>120 μg/mg PTX +<break></break>90 μg/mg silybin i.v.<break></break>every 4 days, 30 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B268-ijms-21-00401" ref-type="bibr">268</xref>]</td></tr><tr><td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Curcumin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT-116 cells in orthotopic mouse model</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 g/kg curcumin by gavage, daily + 60 mg/kg capecitabine by gavage, twice weekly, 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ NF-κB, ↓MMP-2, ↓ CXCR4, ↓ COX-2,<break></break>↓ ICAM-1, ↓VEGF</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B269-ijms-21-00401" ref-type="bibr">269</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Swiss albino rats with N-Nitroso<break></break>N-methyl urea–induced carcinogenesis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pre-treatment with curcumin 50 mg/kg p.o. for one week before administration of irinotecan<break></break>30 μg/mL i.v.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ P-gp,<break></break>↑ sensitivity of cancer cells to irinotecan</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B270-ijms-21-00401" ref-type="bibr">270</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Colorectal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model (6–8 weeks, females) for HCT-116 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.13% Meriva (equivalent to 0.2% curcuminoids) p.o. + 7.5 mg/kg OX i.v. daily, 21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ cancer stem cells,<break></break>↓ DNA damage repair</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B271-ijms-21-00401" ref-type="bibr">271</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse model for PC3 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NPs with 5 mg/kg DOC + 10 mg/kg curcumin i.v. daily,<break></break>21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ intracellular accumulation of DOC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B272-ijms-21-00401" ref-type="bibr">272</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft <italic>nu/nu</italic> mouse models (males, 5–6 weeks old) for PC-3A cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NP with 6 mg/kg DOX + 24 mg/kg curcumin i.v. twice every three days, 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MDR, MRP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B273-ijms-21-00401" ref-type="bibr">273</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model for PC3 cells (nude mice)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 mg/kg curcumin p.o.<break></break>daily, 4 weeks + 160 mg/kg gemcitabine i.p. every 7 days, 21 days + 3 Gy radiation<break></break>days 4, 6, 10 for 21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ MDM2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B274-ijms-21-00401" ref-type="bibr">274</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft mouse model for A549 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day PS +<break></break>500 mg/kg/day curcumin p.o., 36 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ pharmacokinetics<break></break>↑ accumulation in cancer tissue, ↓ P-gp,<break></break>↓ MRP1/2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B275-ijms-21-00401" ref-type="bibr">275</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xenograft BALB/c mouse model (6–8 weeks) for MCF-7 cell lines</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NPs with Tf-PEG-CUR/DOX—50 mg/kg CUR/DOX i.v. once/week, 7 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↑ cellular uptake of DOX</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B276-ijms-21-00401" ref-type="bibr">276</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CRPC patients, non-randomized open-label phase II trial (<italic>n</italic> = 30)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75 mg/m<sup>2</sup> DOC i.v.<break></break>day 1 every 21 days for 6 cycles + 8 mg dexamethasone p.o. 12 h, 3 h and 1 h before DOC administration + 5 mg prednisone p.o. twice/day starting on day 1 + 6000 mg curcumin p.o.<break></break>7 days in each cycle</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ PSA<break></break>(50% of patients),<break></break>↓ NSE (30% of patients),<break></break>suggested mechanisms:<break></break>↓ NF-κB, ↓ AR,<break></break>↓ VEGFR, ↓ MDR1B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B277-ijms-21-00401" ref-type="bibr">277</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Breast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Advanced-metastatic breast cancer patients, single institution open-label phase I trials<break></break>(<italic>n</italic> = 13)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/m<sup>2</sup> DOC i.v.<break></break>day 1 of each 3 weeks cycle for 6 cycles + 450 mg curcumin p.o. 7 days consecutive for each cycle + 50 mg methylprednisolone 2 days before and after chemotherapy</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ CEA, ↓ VEGF<break></break>suggested mechanisms:<break></break>↓ P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B278-ijms-21-00401" ref-type="bibr">278</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Legend—↓—downregulation, ↑—upregulation, COX-2—cicloxygenase 2, MMP-2—metalloproteinase, ICAM-1—intercellular adhesion molecule 1, CXCR4 chemokine receptor type 4, VEGF—vascular endothelial growth factor, DOC—docetaxel, P-gp—P-glycoprotein (MDR1), PS—phospho-sulindac, MRP1/2—multidrugresistance associated protein 1/2, Meriva—turmeric/phospholipid formulation, MDM2—mouse double minute 2 homolog, DOX—doxorubicin (adryamicin), Tf-PEG-CUR—transferrin-poly(ethylene glycol)-curcumin, PTX—paclitaxel, EGFR—epidermal growth factor receptor, EGR-1—early growth response protein 1, MDR—multidrug resistance, CBZ—cabazitaxel, CYP3A4—cytochrome P450 3A4, AKT—protein kinase B, XIAP—inhibitor of apoptosis protein 3, BCRP—breast cancer resistance protein, IGF-1R—insulin growth factor 1 receptor, IAP—inhibitors of apoptosis proteins, cFLIPL—regulator of caspase-8 activation, GRP78—glucose regulated protein, PI3K/AKT—phosphoinositide 3-kinase/protein kinase B, AR—androgen receptor, mTOR—mammalian target of rapamycin, NSCLC—non-small cell lung cancer, p.o.—oral administration, i.v.—intravenous administration, i.p.—intraperitoneal administration, BNDQ—quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles, NPs—nanoparticles, CRPC—castration-resistant prostate cancer, CgA—chromogranin, NSE—neuron-specific enolase, DMBA—7,12-dimethylbenz[a]anthracene, OX—oxaliplatin, CDPP—cisplatin, GF—gefitinib, RES—resveratrol, PPTNPs—podophyllotoxin nanoparticles, CEA—carcioembryonic antigen, TRAIL—TNF-related apoptosis-inducing ligand, ROS—reactive oxygen species, JNK—c-Jun N-terminal kinase, RES—resveratrol, CAPE—caffeic acid phenethyl ester, Nf-kb- nuclear factor kappa-light-chain-enhancer of activated B cells, DPPT—deoxypodophyllotoxin, PSA—prostate serum antigen.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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