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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor</title><author><name sortKey="Chiu, Chang Fang" sort="Chiu, Chang Fang" uniqKey="Chiu C" first="Chang-Fang" last="Chiu">Chang-Fang Chiu</name><affiliation><nlm:aff id="af1-biomolecules-09-00824">Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-09-00824">Cancer Center, China Medical University Hospital, Taichung 40415, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Chin, Hsien Kuo" sort="Chin, Hsien Kuo" uniqKey="Chin H" first="Hsien-Kuo" last="Chin">Hsien-Kuo Chin</name><affiliation><nlm:aff id="af4-biomolecules-09-00824">Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan;<email>cvschin@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Huang, Wei Jan" sort="Huang, Wei Jan" uniqKey="Huang W" first="Wei-Jan" last="Huang">Wei-Jan Huang</name><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Bai, Li Yuan" sort="Bai, Li Yuan" uniqKey="Bai L" first="Li-Yuan" last="Bai">Li-Yuan Bai</name><affiliation><nlm:aff id="af1-biomolecules-09-00824">Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Huang, Hao Yu" sort="Huang, Hao Yu" uniqKey="Huang H" first="Hao-Yu" last="Huang">Hao-Yu Huang</name><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation><affiliation><nlm:aff id="af7-biomolecules-09-00824">Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af8-biomolecules-09-00824">Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715, Taiwan</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31817161</idno><idno type="pmc">6995545</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995545</idno><idno type="RBID">PMC:6995545</idno><idno type="doi">10.3390/biom9120824</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000429</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000429</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor</title><author><name sortKey="Chiu, Chang Fang" sort="Chiu, Chang Fang" uniqKey="Chiu C" first="Chang-Fang" last="Chiu">Chang-Fang Chiu</name><affiliation><nlm:aff id="af1-biomolecules-09-00824">Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-09-00824">Cancer Center, China Medical University Hospital, Taichung 40415, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Chin, Hsien Kuo" sort="Chin, Hsien Kuo" uniqKey="Chin H" first="Hsien-Kuo" last="Chin">Hsien-Kuo Chin</name><affiliation><nlm:aff id="af4-biomolecules-09-00824">Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan;<email>cvschin@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Huang, Wei Jan" sort="Huang, Wei Jan" uniqKey="Huang W" first="Wei-Jan" last="Huang">Wei-Jan Huang</name><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Bai, Li Yuan" sort="Bai, Li Yuan" uniqKey="Bai L" first="Li-Yuan" last="Bai">Li-Yuan Bai</name><affiliation><nlm:aff id="af1-biomolecules-09-00824">Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Huang, Hao Yu" sort="Huang, Hao Yu" uniqKey="Huang H" first="Hao-Yu" last="Huang">Hao-Yu Huang</name><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation></author><author><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name><affiliation><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation><affiliation><nlm:aff id="af7-biomolecules-09-00824">Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff></affiliation><affiliation><nlm:aff id="af8-biomolecules-09-00824">Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715, Taiwan</nlm:aff></affiliation></author></analytic><series><title level="j">Biomolecules</title><idno type="eISSN">2218-273X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC<sub>50</sub> values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (<italic>N</italic>-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F. Bray</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J. Ferlay</name></author><author><name sortKey="Soerjomataram, I" uniqKey="Soerjomataram I">I. Soerjomataram</name></author><author><name sortKey="Siegel, R L" uniqKey="Siegel R">R.L. Siegel</name></author><author><name sortKey="Torre, L A" uniqKey="Torre L">L.A. Torre</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A. Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ziegler, R G" uniqKey="Ziegler R">R.G. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Biomolecules</journal-id><journal-id journal-id-type="iso-abbrev">Biomolecules</journal-id><journal-id journal-id-type="publisher-id">biomolecules</journal-id><journal-title-group><journal-title>Biomolecules</journal-title></journal-title-group><issn pub-type="epub">2218-273X</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31817161</article-id><article-id pub-id-type="pmc">6995545</article-id><article-id pub-id-type="doi">10.3390/biom9120824</article-id><article-id pub-id-type="publisher-id">biomolecules-09-00824</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chiu</surname><given-names>Chang-Fang</given-names></name><xref ref-type="aff" rid="af1-biomolecules-09-00824">1</xref><xref ref-type="aff" rid="af2-biomolecules-09-00824">2</xref><xref ref-type="aff" rid="af3-biomolecules-09-00824">3</xref><xref ref-type="author-notes" rid="fn1-biomolecules-09-00824">†</xref></contrib><contrib contrib-type="author"><name><surname>Chin</surname><given-names>Hsien-Kuo</given-names></name><xref ref-type="aff" rid="af4-biomolecules-09-00824">4</xref><xref ref-type="aff" rid="af5-biomolecules-09-00824">5</xref><xref ref-type="author-notes" rid="fn1-biomolecules-09-00824">†</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Wei-Jan</given-names></name><xref ref-type="aff" rid="af6-biomolecules-09-00824">6</xref><xref ref-type="author-notes" rid="fn1-biomolecules-09-00824">†</xref></contrib><contrib contrib-type="author"><name><surname>Bai</surname><given-names>Li-Yuan</given-names></name><xref ref-type="aff" rid="af1-biomolecules-09-00824">1</xref><xref ref-type="aff" rid="af3-biomolecules-09-00824">3</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Hao-Yu</given-names></name><xref ref-type="aff" rid="af5-biomolecules-09-00824">5</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4934-9126</contrib-id><name><surname>Weng</surname><given-names>Jing-Ru</given-names></name><xref ref-type="aff" rid="af5-biomolecules-09-00824">5</xref><xref ref-type="aff" rid="af6-biomolecules-09-00824">6</xref><xref ref-type="aff" rid="af7-biomolecules-09-00824">7</xref><xref ref-type="aff" rid="af8-biomolecules-09-00824">8</xref><xref rid="c1-biomolecules-09-00824" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-biomolecules-09-00824"><label>1</label>Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</aff><aff id="af2-biomolecules-09-00824"><label>2</label>Cancer Center, China Medical University Hospital, Taichung 40415, Taiwan</aff><aff id="af3-biomolecules-09-00824"><label>3</label>College of Medicine, China Medical University, Taichung 40402, Taiwan</aff><aff id="af4-biomolecules-09-00824"><label>4</label>Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan;<email>cvschin@gmail.com</email></aff><aff id="af5-biomolecules-09-00824"><label>5</label>Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</aff><aff id="af6-biomolecules-09-00824"><label>6</label>Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></aff><aff id="af7-biomolecules-09-00824"><label>7</label>Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</aff><aff id="af8-biomolecules-09-00824"><label>8</label>Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715, Taiwan</aff><author-notes><corresp id="c1-biomolecules-09-00824"><label>*</label>Correspondence: <email>columnster@gmail.com</email></corresp><fn id="fn1-biomolecules-09-00824"><label>†</label><p>These authors contributed equally to this paper.</p></fn></author-notes><pub-date pub-type="epub"><day>04</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>12</month><year>2019</year></pub-date><volume>9</volume><issue>12</issue><elocation-id>824</elocation-id><history><date date-type="received"><day>29</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>11</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</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>Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC<sub>50</sub> values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (<italic>N</italic>-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.</p></abstract><kwd-group><kwd>histone deacetylase</kwd><kwd>HDAC8-selective inhibitor</kwd><kwd>breast cancer</kwd><kwd>apoptosis</kwd><kwd>autophagy</kwd><kwd>PPARγ</kwd><kwd>ROS</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-biomolecules-09-00824"><title>1. Introduction</title><p>Increasing incidences and mortality of breast cancer still remains an unresolved issue in women’s health, with 2.1-million new cases and over 600,000 deaths worldwide in 2018 [<xref rid="B1-biomolecules-09-00824" ref-type="bibr">1</xref>]. Family history of breast cancer, inherited BRCA1 and/or BRCA2 mutations, alcohol intake, and exogenous hormone intake are known risk factors underlying the elevated incidence rate of breast cancer [<xref rid="B2-biomolecules-09-00824" ref-type="bibr">2</xref>]. Despite recent advances in the development of targeted therapy, the overall survival in advanced breast cancer patients remains low at approximately 18% [<xref rid="B3-biomolecules-09-00824" ref-type="bibr">3</xref>], indicating an urgency in developing new therapeutic strategies.</p><p>As substantial evidence has linked dysregulation of histone deacetylases with tumorigenesis [<xref rid="B4-biomolecules-09-00824" ref-type="bibr">4</xref>,<xref rid="B5-biomolecules-09-00824" ref-type="bibr">5</xref>], HDAC inhibitors have emerged as potential therapeutic agents for multiple types of human cancer due to their diverse modes of antitumor mechanisms [<xref rid="B6-biomolecules-09-00824" ref-type="bibr">6</xref>]. For example, the FDA-approved HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) [<xref rid="B7-biomolecules-09-00824" ref-type="bibr">7</xref>] was reported to inhibit cell growth by increasing HSP60 nitration and reactive oxygen species (ROS) production in lung cancer cells [<xref rid="B8-biomolecules-09-00824" ref-type="bibr">8</xref>]. SAHA was also shown to synergize with the PARP inhibitor Olaparib in triple-negative breast cancer (TNBC) in vitro and in vivo by inducing apoptosis and autophagic cell death [<xref rid="B9-biomolecules-09-00824" ref-type="bibr">9</xref>]. Evidence has shown clinical benefits of using SAHA in 40% of advanced tamoxifen-resistant breast cancer patients [<xref rid="B10-biomolecules-09-00824" ref-type="bibr">10</xref>].</p><p>Among 11 Zn<sup>2+</sup>-dependent HDAC isozymes, HDAC8 was found immunoreactive in 85% of breast cancer patients [<xref rid="B11-biomolecules-09-00824" ref-type="bibr">11</xref>,<xref rid="B12-biomolecules-09-00824" ref-type="bibr">12</xref>]. An et al. demonstrated that HDAC8 inhibitor PCI34051 suppressed the migration of breast cancer cells by facilitating the degradation of YAP [<xref rid="B13-biomolecules-09-00824" ref-type="bibr">13</xref>]. In this study, we report the characterization of the anti-tumor activity and underlying mechanisms of a novel HDAC8 inhibitor, (<italic>E</italic>)-<italic>N</italic>-hydroxy-4-methoxy-2-(3,4-methylenedioxyphenyl)cinnamide (HMC) (<xref ref-type="fig" rid="biomolecules-09-00824-f001">Figure 1</xref>A and <xref ref-type="app" rid="app1-biomolecules-09-00824">Figure S1</xref>) [<xref rid="B14-biomolecules-09-00824" ref-type="bibr">14</xref>], in breast cancer cells.</p></sec><sec sec-type="results" id="sec2-biomolecules-09-00824"><title>2. Results</title><sec id="sec2dot1-biomolecules-09-00824"><title>2.1. HMC Inhibits the Viability of Breast Cancer Cells and Modulates HDAC Expression</title><p>We used two breast cancer cell lines, MCF-7 and MDA-MB-231, to interrogate the anti-proliferative effect of HMC. MTT assays showed that the dose-dependent suppressive effect of HMC on the viability of MCF-7 and MDA-MB-231 cells with IC<sub>50</sub> values of 7.7 μM and 9.5 μM, respectively, after 48 h of treatment (<xref ref-type="fig" rid="biomolecules-09-00824-f001">Figure 1</xref>B; etoposide as the positive control). Additionally, the non-tumorgenic human breast epithelial cell line H184B5F5/M10 was less sensitive to HMC with an IC50 value of 14.1 μM (right panel of <xref ref-type="fig" rid="biomolecules-09-00824-f001">Figure 1</xref>B). Western blot analysis of HMC-treated MCF-7 and MDA-MB-231 cell lysates shows that this antiproliferative effect was associated with histone H3 hyperacetylation, reflecting the effect of HDAC8 inhibition (<xref ref-type="fig" rid="biomolecules-09-00824-f001">Figure 1</xref>C). Interestingly, HMC treatment led to decreases in HDAC8 expression which is similar to the finding of PCI34051 in angiotension-II-induced hypertensive mice [<xref rid="B15-biomolecules-09-00824" ref-type="bibr">15</xref>], while the level of HDAC1 remained largely unchanged in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f001">Figure 1</xref>C).</p></sec><sec id="sec2dot2-biomolecules-09-00824"><title>2.2. HMC Induces Apoptosis</title><p>Several lines of evidence indicate that the antiproliferative effect of HMC was attributable to its ability to induce apoptosis in MCF-7 cells. For example, flow cytometric analysis of Annexin V/PI staining shows increases in annexin V-positive cells in response to HMC treatment in a concentration-dependent manner (<xref ref-type="fig" rid="biomolecules-09-00824-f002">Figure 2</xref>A,B; staurosporine as the positive control). In addition, flow cytometry demonstrated that HMC dose-dependently increases caspase-3 activities in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f002">Figure 2</xref>C), and Western blot analysis showed increased levels of the cleavage PARP and caspase-9, accompanied by decreased expression of procaspase-8 (<xref ref-type="fig" rid="biomolecules-09-00824-f002">Figure 2</xref>D).</p></sec><sec id="sec2dot3-biomolecules-09-00824"><title>2.3. HMC Inhibits the Akt/mTOR Signaling Pathway and Activates PPARγ</title><p>Previously, it has been reported that the pan-HDAC inhibitor LAQ824 inhibited cell growth, in part, through the inhibition of Akt activation in prostate cancer cells [<xref rid="B16-biomolecules-09-00824" ref-type="bibr">16</xref>,<xref rid="B17-biomolecules-09-00824" ref-type="bibr">17</xref>]. In light of the importance of Akt in breast cancer tumorigenesis and metastasis [<xref rid="B16-biomolecules-09-00824" ref-type="bibr">16</xref>,<xref rid="B17-biomolecules-09-00824" ref-type="bibr">17</xref>], we analyzed the effect of HMC on the activation status of Akt signaling. Western blotting revealed that HMC treatment led to decreased phosphorylation of Akt and it’s down-stream effector mTOR in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f003">Figure 3</xref>A). In addition, HMC up-regulated the expression of the pro-apoptotic protein Bax, accompanied by reduced expression of the anti-apoptotic proteins Mcl-1 and Bcl-2 (<xref ref-type="fig" rid="biomolecules-09-00824-f003">Figure 3</xref>A).</p><p>It has been reported that pharmacological inhibition of HDACs led to the activation of the peroxisome proliferator-activated receptor (PPAR)γ, a member of nuclear receptors associated with lipogenesis and cell metabolism [<xref rid="B18-biomolecules-09-00824" ref-type="bibr">18</xref>]. In addition, the HDAC8 inhibitor NCC170 was shown to ameliorate idiopathic pulmonary fibrosis, in part, by increasing PPARγ expression [<xref rid="B19-biomolecules-09-00824" ref-type="bibr">19</xref>]. Here, the effect of HMC on PPARγ was assessed using an established PPRE-luciferase reporter assay in MCF7- cells [<xref rid="B20-biomolecules-09-00824" ref-type="bibr">20</xref>]. Compared with the known PPARγ agonist troglitazone, HMC showed a greater degree of PPARγ promotor transactivation in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f003">Figure 3</xref>B). Western blot analysis showed that HMC increased PPARγ expression in MCF-7 cells, while decreasing the levels of the PPARγ-targeted gene products cyclin D1 and CDK6, both of which are associated with cell cycle regulation in MCF-7 cells [<xref rid="B21-biomolecules-09-00824" ref-type="bibr">21</xref>,<xref rid="B22-biomolecules-09-00824" ref-type="bibr">22</xref>] (<xref ref-type="fig" rid="biomolecules-09-00824-f003">Figure 3</xref>C). The expression of cyclin D1 and CDK6 remained unchanged in MDA-MB-231 cells treated with HMC for 48 h (<xref ref-type="fig" rid="biomolecules-09-00824-f003">Figure 3</xref>C).</p></sec><sec id="sec2dot4-biomolecules-09-00824"><title>2.4. HMC Increases ROS Generation</title><p>Previous studies have linked ROS production with the antiproliferative effect of pan-HDAC inhibitors [<xref rid="B23-biomolecules-09-00824" ref-type="bibr">23</xref>,<xref rid="B24-biomolecules-09-00824" ref-type="bibr">24</xref>]. As shown in <xref ref-type="fig" rid="biomolecules-09-00824-f004">Figure 4</xref>A, HMC increased ROS production in MCF-7 cells after 24 h of treatment (H<sub>2</sub>O<sub>2</sub> as the positive control). In addition, pre-treatment with an ROS inhibitor, <italic>N</italic>-acetylcysteine (NAC) or glutathione (GSH), for 15 min could reverse HMC-induced ROS generation (<xref ref-type="fig" rid="biomolecules-09-00824-f004">Figure 4</xref>A). We also examined the antiproliferative effects of HMC with or without NAC or GSH in MCF-7 cells using MTT assay (S2, <xref ref-type="app" rid="app1-biomolecules-09-00824">Figure S2</xref>). Although HMC reduced the cell viability, addition of NAC or GSH did not increase the HMC-mediated cytotoxicity. Furthermore, HMC increased the phosphorylation of H2AX, a biomarker in response to DNA damage [<xref rid="B25-biomolecules-09-00824" ref-type="bibr">25</xref>], in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f004">Figure 4</xref>B).</p></sec><sec id="sec2dot5-biomolecules-09-00824"><title>2.5. HMC Induces Autophagy</title><p>Substantial evidence has shown the ability of pan-HDAC inhibitors to promote autophagy [<xref rid="B26-biomolecules-09-00824" ref-type="bibr">26</xref>,<xref rid="B27-biomolecules-09-00824" ref-type="bibr">27</xref>]. During autophagy, the formation of acidic vesicular organelles (AVOs) is one of the characteristic features of cells engaged in autophagy in response to starvation or radiation [<xref rid="B28-biomolecules-09-00824" ref-type="bibr">28</xref>]. Thus, we examine drug-induced cellular acidification by using acridine orange staining, in which cytoplasm fluorescence changed from bright green to bright red. As shown in <xref ref-type="fig" rid="biomolecules-09-00824-f005">Figure 5</xref>A,B, the generation of AVOs increased after the treatment of HMC in a concentration-dependent manner in MCF-7 cells (rapamycin as the positive control). In addition, immunoblotting shows HMC-induced increases in the expression of LC3B-II and autophagy-related (Atg)5 in MCF-7 cells (<xref ref-type="fig" rid="biomolecules-09-00824-f005">Figure 5</xref>C), both of which are important markers for autophagosome formation [<xref rid="B29-biomolecules-09-00824" ref-type="bibr">29</xref>,<xref rid="B30-biomolecules-09-00824" ref-type="bibr">30</xref>]. In addition, time-course experiments demonstrated that LC3B-II expression increased after 6 h of HMC treatment (<xref ref-type="fig" rid="biomolecules-09-00824-f005">Figure 5</xref>D).</p></sec><sec id="sec2dot6-biomolecules-09-00824"><title>2.6. Inhibition of Autophagy Reversed HMC-Induced Apoptosis in MCF-7 Cells</title><p>To further investigate the role of autophagy in HMC-induced cell death, we examined the effect of pharmacological inhibition of autophagy on HMC-induced apoptosis in MCF-7 cells. As shown in <xref ref-type="fig" rid="biomolecules-09-00824-f006">Figure 6</xref>, co-treatment with the autophagic inhibitor 3-methyladenine A (3-MA) or chloroquine (CQ) could significantly reduce the extent of apoptosis induced by HMC.</p></sec></sec><sec sec-type="discussion" id="sec3-biomolecules-09-00824"><title>3. Discussion</title><p>In the present study, we investigated the antitumor effect of a novel HDAC8-selective inhibitor HMC in breast cancer cells. In addition to inhibiting HDAC8 deacetylase activity (IC50 values of 200.7±0.3 nM and 798.4±0.3 nM using recombinant HDAC8 and HeLa nuclear extracts, respectively) [<xref rid="B14-biomolecules-09-00824" ref-type="bibr">14</xref>], HMC could also downregulate HDAC8 expression in MCF-7 cells while not affecting HDAC1 expression. These data suggest that HMC might mediate its inhibitory effect on HDAC8 through two different mechanisms. Theses evidence suggests that HMC induced both apoptosis and autophagy in MCF-7 cells, and that concomitant treatment with autophagy inhibitors could attenuate HMC-induced apoptosis.</p><p>Although apoptosis is characteristic of pan-HDAC inhibitor-mediated anticancer effects [<xref rid="B9-biomolecules-09-00824" ref-type="bibr">9</xref>,<xref rid="B31-biomolecules-09-00824" ref-type="bibr">31</xref>,<xref rid="B32-biomolecules-09-00824" ref-type="bibr">32</xref>], the role of HDAC8 in this programmed cell death event remains to be elucidated. In this study, we obtained evidence that selective inhibition of HDAC8 by HMC was effective in inducing mitochondria-dependent apoptosis, as manifested by Annexin V-PI staining, activation of caspase-3 and caspase-9, and PARP cleavage. Mechanistically, the proapoptotic effect of HMC shared many features of that of pan-HDAC inhibitors. For example, HMC was effective in inhibiting the Akt-mTOR signaling pathway, which led to increases in the expression levels of the proapoptotic protein Bax and decreased the expression of antiapoptotic proteins Mcl-1 and Bcl-2. Consistent with the reported role of pan-HDAC inhibitors in regulating the activity and expression of PPARγ [<xref rid="B33-biomolecules-09-00824" ref-type="bibr">33</xref>,<xref rid="B34-biomolecules-09-00824" ref-type="bibr">34</xref>], we also demonstrated the ability of HMC to enhance PPARγ transactivation activity and to modulate the expression of PPARγ and PPARγ-regulated gene products. These results suggested that Akt/mTOR and PPARγ signaling pathways might be partially responsible for the cell growth inhibition in HMC-treated MCF-7 cells.</p><p>ROS generation represents a major mechanism by which many therapeutic agents exert their antitumor effects [<xref rid="B35-biomolecules-09-00824" ref-type="bibr">35</xref>,<xref rid="B36-biomolecules-09-00824" ref-type="bibr">36</xref>]. Several reports showed that pan-HDAC inhibitors increased ROS levels in solid tumors and liquid tumors [<xref rid="B23-biomolecules-09-00824" ref-type="bibr">23</xref>,<xref rid="B37-biomolecules-09-00824" ref-type="bibr">37</xref>]. For example, Dahabieh et al. reported that SAHA induced apoptosis through increasing ROS generation in lymphoma cells [<xref rid="B37-biomolecules-09-00824" ref-type="bibr">37</xref>]. Similarly, we also noted increased ROS-production in HMC-treated MCF-7 cells. As HDACs are known to potentiate DNA damage repair capacity, pan-HDAC inhibitors are potent inducers of DNA damage in transformed cells [<xref rid="B38-biomolecules-09-00824" ref-type="bibr">38</xref>]. For example, the class I HDAC inhibitor depsipeptide caused DNA damage through ROS generation in cancer cells [<xref rid="B39-biomolecules-09-00824" ref-type="bibr">39</xref>]. Our results demonstrated that HMC increased the phosphorylation of H2AX, an early response after the formation of DNA double strand breaks [<xref rid="B35-biomolecules-09-00824" ref-type="bibr">35</xref>].</p><p>Autophagy, a cell recycling process, allows cells to survive from starvation and plays an important role in various physiological condition [<xref rid="B40-biomolecules-09-00824" ref-type="bibr">40</xref>]. Dysregulation of autophagy led to diseases including neurodegeneration, aging, immunological diseases, and cancer [<xref rid="B41-biomolecules-09-00824" ref-type="bibr">41</xref>,<xref rid="B42-biomolecules-09-00824" ref-type="bibr">42</xref>]. Kundu et.al reported that targeting autophagy provides a viable strategy for the treatment of Alzheimer’s disease [<xref rid="B42-biomolecules-09-00824" ref-type="bibr">42</xref>]. Due to the autophagy-inducing ability of HMC which suggested its potential as the treatment of inflammatory and neurodegenerative diseases which warrants further investigations.</p><p>It is found that knockdown of HDAC8 promotes autophagy which relates to the inhibition of growth in oral cancer cells [<xref rid="B43-biomolecules-09-00824" ref-type="bibr">43</xref>]. We found that autophagy is an early response after the treatment of HMC for 6 h in MCF-7 cells. Previous studies have revealed that knockdown of Atg could increase the cytotoxicity of pan-HDAC inhibitors, which suggested that autophagy might serve as a prosurvival mechanism [<xref rid="B44-biomolecules-09-00824" ref-type="bibr">44</xref>,<xref rid="B45-biomolecules-09-00824" ref-type="bibr">45</xref>]. Our observation that autophagic inhibitors could protect cells from HMC-induced apoptosis is consistent with this notion [<xref rid="B46-biomolecules-09-00824" ref-type="bibr">46</xref>,<xref rid="B47-biomolecules-09-00824" ref-type="bibr">47</xref>]. Substantial evidence reveals that the potential mechanisms between autophagy and apoptosis including endoplasmic reticulum stress [<xref rid="B48-biomolecules-09-00824" ref-type="bibr">48</xref>], PI3K/mTOR [<xref rid="B49-biomolecules-09-00824" ref-type="bibr">49</xref>], and Bcl-2 [<xref rid="B50-biomolecules-09-00824" ref-type="bibr">50</xref>] in cancer cells. A previous study showed that Bcl-2 would be displaced from Beclin-1 and Bax to induce autophagy and apoptosis under conditions of stress [<xref rid="B51-biomolecules-09-00824" ref-type="bibr">51</xref>]. It’s possible that the ability of HMC to modulate the Akt/mTOR and Bcl-2 pathways plays a role in the crosstalk between autophagy and apoptosis.</p><p>In conclusion, our study showed that HMC induced caspase-dependent apoptosis via inhibition of Akt/mTOR signaling, caused DNA damage through ROS production, induced PPARγ activation and autophagy. Together, these findings suggest the potential of using HMC as a scaffold to develop potent HDAC8 inhibitors for breast cancer therapy.</p></sec><sec id="sec4-biomolecules-09-00824"><title>4. Materials and Methods</title><sec id="sec4dot1-biomolecules-09-00824"><title>4.1. Reagents, Chemicals, Antibodies</title><p>HMC was synthesized and characterized as previous report (S1, <xref ref-type="app" rid="app1-biomolecules-09-00824">Figure S1</xref>) [<xref rid="B14-biomolecules-09-00824" ref-type="bibr">14</xref>]. All agents were dissolved in DMSO, diluted in culture medium, and added to cells at a final DMSO concentration of 0.1%. The peroxisome proliferator-activated receptor response element (PPRE) x3-TK-Luc plasmids were purchased from Addgene (Cambridge, MA). Other chemicals and reagents were obtained from Sigma-Aldrich unless otherwise noted.</p></sec><sec id="sec4dot2-biomolecules-09-00824"><title>4.2. Cell Culture</title><p>Human breast cancer cell lines (MCF-7 and MDA-MB-231) were purchased from the American Type Culture Collection (Manasas, VA, USA). Non-tumorgenic human breast epithelial cell line (H184B5F5/M10) was kindly provided from Dr. Ming-Hong Tai (National Sun Yat-sen University). MCF-7 and MDA-MB-231 cells were cultured in DMEM/F12 (Invitrogen, Carlsbad, CA); and supplemented with 10% heat-inactivated fetal bovine serum (FBS; Gibco, Grand Island, NY) at 37 °C in a humidified incubator with 5% CO<sub>2</sub>. H184B5F5/M10 cells were maintained in α-MEM medium with the same supplements and culture condition.</p></sec><sec id="sec4dot3-biomolecules-09-00824"><title>4.3. Cell Viability Analysis</title><p>Cell viability of HMC was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays [<xref rid="B20-biomolecules-09-00824" ref-type="bibr">20</xref>]. Briefly, 100 μL of 0.5 mg/mL MTT was added to each well plated 96-well plate and incubated for 4 h at 37 °C. Medium was removed and the reduced MTT dye was solubilized in 200 μL/well DMSO. A SPECTROstar Nano spectrophotometer (BMG LABTECH, Ortenberg, Germany) was used to measure the absorbance at 570 nm.</p></sec><sec id="sec4dot4-biomolecules-09-00824"><title>4.4. Flow Cytometry</title><p>For apoptosis assay, apoptotic cells were detected as described previously [<xref rid="B52-biomolecules-09-00824" ref-type="bibr">52</xref>] using a commercial kit (BD Pharmingen, San Diego, USA) following the manufacturer’s instructions by flow cytometry (Attune NxT flow cytometer, ThermoFisher Scientific, Waltham, MA, USA). For caspase-3 activation, cells were seeded in 6-well culture plates and treated with DMSO or HMC at the indicated concentrations for 48 h. Then, the caspase-3 activity were assessed using a FITC rabbit anti-active caspase-3 kit (BD Pharmingen) according to the manufacturer’s protocol. ROS production were examined using the fluorescence probe 2’, 7’-dichlorodihyrofluorescein diacetate (H2DCFDA) [<xref rid="B53-biomolecules-09-00824" ref-type="bibr">53</xref>].</p></sec><sec id="sec4dot5-biomolecules-09-00824"><title>4.5. Western Blot</title><p>Total cellular protein was isolated from the cells after various treatments. For Western blots, a previously described procedure was applied [<xref rid="B54-biomolecules-09-00824" ref-type="bibr">54</xref>]. The following primary antibodies were used: Acetyl Histone H3, HDAC1, HDAC8, PPARγ, cyclin D1, CDK6, p-Ser<sup>473</sup> Akt, Akt, p-Ser<sup>2448</sup> mTOR, mTOR, p-Ser<sup>139</sup> H2AX, H2AX, Bax, Mcl-1, PARP, procaspase-8, cleaved caspase-9, LC3B, and Atg5 were purchased from Cell Signaling Technologies (Beverly, MA, USA); β-actin, Sigma-Aldrich (St. Louis, MO, USA). The secondary antibodies were purchased from Santa Cruz Biotechnology. The enhanced chemiluminescence (ECL) system for detection of immunoblotted proteins was from GE Healthcare Bioscience (Piscataway, NJ, USA). Then, the protein was visualized by FUSION SOLO S (VILBER, Deutschland, Germany).</p></sec><sec id="sec4dot6-biomolecules-09-00824"><title>4.6. Acridine Orange Staining</title><p>MCF-7 cells (2 × 10<sup>5</sup>) were plated on coverslips and allowed to attach. Following treatment with DMSO (control) or HMC at the indicated concentration or rapamycin (100 nM) for 24 h, cells were stained with 1 μg/mL acridine orange for 15 min, washed with PBS, and examined under a ZEISS fluorescence microscope at ×200 objective lens magnification. The percentage of AVOs (dots with clear yellow or red fluorescence) was calculated using at least 100 cells per image in each condition under fluorescence microscopy.</p></sec><sec id="sec4dot7-biomolecules-09-00824"><title>4.7. Transient Transfection of PPARγ</title><p>Plasmids were transiently transfected into cells by using Fugene HD reagent (Roche, Mannheim, Germany) according to the manufacture’s protocol. After 24 h, transfected cell were treated with DMSO or HMC, and subjected to fluorescence analysis [<xref rid="B20-biomolecules-09-00824" ref-type="bibr">20</xref>].</p></sec><sec id="sec4dot8-biomolecules-09-00824"><title>4.8. Statistical Analysis</title><p>All experiments were performed in three replicates. Statistical significance was determined with Student’s <italic>t</italic> test comparison between two groups of data sets. Differences between groups were considered significant at * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01.</p></sec></sec></body><back><ack><title>Acknowledgments</title><p>This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 106-2320-B-110-003-MY3), the Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence, Taiwan (MOHW108-TDU-B-212-112015, MOHW108-TDU-B-212-124026), the National Health Research Institutes, Taiwan (NHRI-108A1-CACO-13191902), China Medical University Hospital, Taiwan (DMR-109-014), and Kaohsiung Armed Forces General Hospital (KAFGH_10812), Taiwan.</p></ack><app-group><app id="app1-biomolecules-09-00824"><title>Supplementary Materials</title><p>The following are available online at <uri xlink:href="https://www.mdpi.com/2218-273X/9/12/824/s1">https://www.mdpi.com/2218-273X/9/12/824/s1</uri>, Figure S1: The synthetic procedure of HMC. Figure S2: Effects of 5 μM HMC or in combination of 5 mM <italic>N</italic>-acetylcysteine (NAC) or 500 μM glutathione (GSH) in MCF-7 cells for 24 h, and cell viability was determined by MTT assay.</p><supplementary-material content-type="local-data" id="biomolecules-09-00824-s001"><media xlink:href="biomolecules-09-00824-s001.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></app></app-group><notes><title>Author Contributions</title><p>C.-F.C. and H.-K.C. interpreted some data. The synthesis and characterization of HMC and the <xref ref-type="app" rid="app1-biomolecules-09-00824">supporting information</xref> were made by W.-J.H., L.-Y.B. performed the statistical analyses. Some of the experiments were performed by H.-Y.H., J.-R.W. prepared the figures, interpreted some data, and wrote the manuscript.</p></notes><notes><title>Funding</title><p>Ministry of Science and Technology: MOST 106-2320-B-110-003-MY3, the Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence: MOHW108-TDU-B-212-112015, MOHW108-TDU-B-212-124026, the National Health Research Institutes: NHRI-108A1-CACO-13191902, and Kaohsiung Armed Forces General Hospital: KAFGH_10812, Taiwan.</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no competing financial interests.</p></notes><glossary><title>Abbreviations</title><p>histone deacetylases (HDACs); suberoylanilide hydroxamic acid (SAHA); trichostatin A (TSA); reactive oxygen species (ROS); peroxisome proliferator-activated receptor response element (PPRE); fetal bovine serum (FBS); phosphate-buffered saline (PBS); peroxisome proliferator-activated receptor (PPAR); autophagy-related (Atg); Yes-associated protein (YAP); acidic vesicular organelles (AVOs); autophagy-related (Atg); 3-methyladenine A (3-MA); chloroquine (CQ); <italic>N</italic>-acetylcysteine (NAC); glutathione (GSH).</p></glossary><ref-list><title>References</title><ref id="B1-biomolecules-09-00824"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bray</surname><given-names>F.</given-names></name><name><surname>Ferlay</surname><given-names>J.</given-names></name><name><surname>Soerjomataram</surname><given-names>I.</given-names></name><name><surname>Siegel</surname><given-names>R.L.</given-names></name><name><surname>Torre</surname><given-names>L.A.</given-names></name><name><surname>Jemal</surname><given-names>A.</given-names></name></person-group><article-title>Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries</article-title><source>CA Cancer J. 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Points, means; bars, SD (n = 4–6). * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01. (<bold>C</bold>) Western blot analysis of acetyl Histone H3, HDAC1, and HDAC8 in HMC-treated cells for 48 h. Left panel, MCF-7 cells. Right panel, MDA-MB-231 cells. The values in percentage or fold denote the relative intensity of protein bands of HMC treated samples to that of the respective DMSO vehicle control after being normalized to the respective internal reference (β-actin).</p></caption><graphic xlink:href="biomolecules-09-00824-g001"></graphic></fig><fig id="biomolecules-09-00824-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>HMC induces apoptosis in MCF-7 cells. (<bold>A</bold>) Cells were treated with DMSO or HMC or staurosporine (Stauro.) for 48 h, and stained with propidium iodide (PI)/annexin V. (<bold>B</bold>) Statistically analysis of apoptotic cells (Q2+Q4) after the treatment of HMC for 48 h. Points, means; bars, SD (n = 4) * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01. (<bold>C</bold>) Caspase-3 activation after the treatment of HMC for 48 h. Cells were collected after the treatment of DMSO or HMC and detected using flow cytometry as Materials and methods. Points, means; bars, SD (n = 3) * <italic>p</italic> < 0.05. (<bold>D</bold>) Expression of PARP, procaspase-8, and cleaved caspase-9 in HMC-treated cells. Total cell lysates were collected as Materials and methods. The values in percentage or fold denote the relative intensity of protein bands of HMC treated samples to that of the respective DMSO vehicle control after being normalized to β-actin.</p></caption><graphic xlink:href="biomolecules-09-00824-g002"></graphic></fig><fig id="biomolecules-09-00824-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>HMC modulates the expression of various biomarkers in breast cancer cells. (<bold>A</bold>) Phosphorylation/expression of Akt, mTOR, Bax, Mcl-1, and Bcl-2 after the treatment of HMC in MCF-7 cells. (<bold>B</bold>) <italic>PPAR</italic><italic>γ</italic> promoter transactivation in HMC-treated MCF-7 cells. 50 μM troglitazone (TRO) was used as positive control. (<bold>C</bold>) Levels of PPAR<italic>γ</italic>, cyclin D1, and CDK6 in HMC-treated cells for 48 h. Left panel, MCF-7 cells. Right panel, MDA-MB-231 cells. The values in percentage or fold denote the relative intensity of protein bands of HMC treated samples to that of the respective DMSO vehicle control after being normalized to the respective internal reference (total respective protein or β-actin).</p></caption><graphic xlink:href="biomolecules-09-00824-g003"></graphic></fig><fig id="biomolecules-09-00824-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>HMC increased reactive oxygen species (ROS) production. (<bold>A</bold>) Cells were treat with HMC alone or in combination of 5 mM <italic>N</italic>-acetylcysteine (NAC) or 500 μM glutathione (GSH) for 24 h. 300 μM H<sub>2</sub>O<sub>2</sub> was used as positive control. SD (n = 3) * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01. (<bold>B</bold>) Effects of HMC on the phosphorylation and expression of H2AX in MCF-7 cells. The values in fold denote the relative intensity of protein bands of HMC treated samples to that of the respective DMSO vehicle control after being normalized to the respective internal reference (total respective protein).</p></caption><graphic xlink:href="biomolecules-09-00824-g004"></graphic></fig><fig id="biomolecules-09-00824-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>HMC induces autophagy. (<bold>A</bold>) Fluorescence microscopy following acridine orange staining revealed an increase in the number of cytoplasmic acidic vesicular organelles (AVOs) in MCF-7 cells for 24 h. 100 nM Rapamycin (RAP) was used as positive control. arrows: acidic vesicular organelles. magnification: 200×. (<bold>B</bold>) Quantitative data calculated percentage of AVO staining cells after the treatment of HMC. At least 100 cells from each treatment group were calculated per image under fluorescence microscopy. Data are represented as the mean ± SD. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01. (<bold>C</bold>) Effect of HMC on the expression of LC3B and Atg5 in MCF-7 cells. (<bold>D</bold>) Time-dependent effect of HMC on the expression of LC3B. The values in percentage or fold denote the relative intensity of protein bands of HMC treated samples to that of the respective DMSO vehicle control after being normalized to β-actin.</p></caption><graphic xlink:href="biomolecules-09-00824-g005"></graphic></fig><fig id="biomolecules-09-00824-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Co-treatment of autophagic inhibitor partially reversed HMC-induced apoptosis. MCF-7 cells were treated with HMC alone or in combination of 3-methyladenine (3-MA) or chloroquine (CQ) for 48 h and stained with propidium iodide (PI)/annexin V. SD (n = 4) * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01.</p></caption><graphic xlink:href="biomolecules-09-00824-g006"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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