Hydroxychloroquine enhances the antitumor effects of BC001 in gastric cancer
Identifieur interne : 000634 ( Pmc/Curation ); précédent : 000633; suivant : 000635Hydroxychloroquine enhances the antitumor effects of BC001 in gastric cancer
Auteurs : Wei Wang ; Linqing Liu ; Yucheng Zhou ; Qiang Ye ; Xiuli Yang ; Jinying Jiang ; Ziqi Ye [République populaire de Chine] ; Feng Gao [République populaire de Chine] ; Xiaolu Tan [République populaire de Chine] ; Guobing Zhang ; Qingxia Fang ; Zixue XuanSource :
- International Journal of Oncology [ 1019-6439 ] ; 2019.
Abstract
Gastric cancer is an important cancer type worldwide, the anti-angiogenic agent BC001 can target the vascular endothelial growth factor receptor 2 (VEGFR2), and significantly suppresses the growth of gastric cancer BGC823 cells
Url:
DOI: 10.3892/ijo.2019.4824
PubMed: 31268153
PubMed Central: 6615922
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Wei Wang<affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af2-ijo-55-02-0405">Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001</nlm:aff><wicri:noCountry code="subfield">Anhui 230001</wicri:noCountry></affiliation><affiliation><nlm:aff id="af3-ijo-55-02-0405">Department of General Surgery, Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hydroxychloroquine enhances the antitumor effects of BC001 in gastric cancer</title><author><name sortKey="Wang, Wei" sort="Wang, Wei" uniqKey="Wang W" first="Wei" last="Wang">Wei Wang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Liu, Linqing" sort="Liu, Linqing" uniqKey="Liu L" first="Linqing" last="Liu">Linqing Liu</name><affiliation><nlm:aff id="af2-ijo-55-02-0405">Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001</nlm:aff><wicri:noCountry code="subfield">Anhui 230001</wicri:noCountry></affiliation></author><author><name sortKey="Zhou, Yucheng" sort="Zhou, Yucheng" uniqKey="Zhou Y" first="Yucheng" last="Zhou">Yucheng Zhou</name><affiliation><nlm:aff id="af3-ijo-55-02-0405">Department of General Surgery, Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Ye, Qiang" sort="Ye, Qiang" uniqKey="Ye Q" first="Qiang" last="Ye">Qiang Ye</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Yang, Xiuli" sort="Yang, Xiuli" uniqKey="Yang X" first="Xiuli" last="Yang">Xiuli Yang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Jiang, Jinying" sort="Jiang, Jinying" uniqKey="Jiang J" first="Jinying" last="Jiang">Jinying Jiang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Ye, Ziqi" sort="Ye, Ziqi" uniqKey="Ye Z" first="Ziqi" last="Ye">Ziqi Ye</name><affiliation wicri:level="4"><nlm:aff id="af4-ijo-55-02-0405">Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003</nlm:aff><orgName type="university">Université de Zhejiang</orgName><country>République populaire de Chine</country><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name><affiliation wicri:level="1"><nlm:aff id="af5-ijo-55-02-0405">Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Xiaolu" sort="Tan, Xiaolu" uniqKey="Tan X" first="Xiaolu" last="Tan">Xiaolu Tan</name><affiliation wicri:level="1"><nlm:aff id="af5-ijo-55-02-0405">Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Guobing" sort="Zhang, Guobing" uniqKey="Zhang G" first="Guobing" last="Zhang">Guobing Zhang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Fang, Qingxia" sort="Fang, Qingxia" uniqKey="Fang Q" first="Qingxia" last="Fang">Qingxia Fang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Xuan, Zixue" sort="Xuan, Zixue" uniqKey="Xuan Z" first="Zixue" last="Xuan">Zixue Xuan</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31268153</idno><idno type="pmc">6615922</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615922</idno><idno type="RBID">PMC:6615922</idno><idno type="doi">10.3892/ijo.2019.4824</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000634</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000634</idno><idno type="wicri:Area/Pmc/Curation">000634</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000634</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hydroxychloroquine enhances the antitumor effects of BC001 in gastric cancer</title><author><name sortKey="Wang, Wei" sort="Wang, Wei" uniqKey="Wang W" first="Wei" last="Wang">Wei Wang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Liu, Linqing" sort="Liu, Linqing" uniqKey="Liu L" first="Linqing" last="Liu">Linqing Liu</name><affiliation><nlm:aff id="af2-ijo-55-02-0405">Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001</nlm:aff><wicri:noCountry code="subfield">Anhui 230001</wicri:noCountry></affiliation></author><author><name sortKey="Zhou, Yucheng" sort="Zhou, Yucheng" uniqKey="Zhou Y" first="Yucheng" last="Zhou">Yucheng Zhou</name><affiliation><nlm:aff id="af3-ijo-55-02-0405">Department of General Surgery, Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Ye, Qiang" sort="Ye, Qiang" uniqKey="Ye Q" first="Qiang" last="Ye">Qiang Ye</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Yang, Xiuli" sort="Yang, Xiuli" uniqKey="Yang X" first="Xiuli" last="Yang">Xiuli Yang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Jiang, Jinying" sort="Jiang, Jinying" uniqKey="Jiang J" first="Jinying" last="Jiang">Jinying Jiang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Ye, Ziqi" sort="Ye, Ziqi" uniqKey="Ye Z" first="Ziqi" last="Ye">Ziqi Ye</name><affiliation wicri:level="4"><nlm:aff id="af4-ijo-55-02-0405">Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003</nlm:aff><orgName type="university">Université de Zhejiang</orgName><country>République populaire de Chine</country><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name><affiliation wicri:level="1"><nlm:aff id="af5-ijo-55-02-0405">Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Xiaolu" sort="Tan, Xiaolu" uniqKey="Tan X" first="Xiaolu" last="Tan">Xiaolu Tan</name><affiliation wicri:level="1"><nlm:aff id="af5-ijo-55-02-0405">Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Guobing" sort="Zhang, Guobing" uniqKey="Zhang G" first="Guobing" last="Zhang">Guobing Zhang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Fang, Qingxia" sort="Fang, Qingxia" uniqKey="Fang Q" first="Qingxia" last="Fang">Qingxia Fang</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author><author><name sortKey="Xuan, Zixue" sort="Xuan, Zixue" uniqKey="Xuan Z" first="Zixue" last="Xuan">Zixue Xuan</name><affiliation><nlm:aff id="af1-ijo-55-02-0405">Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</nlm:aff><wicri:noCountry code="subfield">Zhejiang 310014</wicri:noCountry></affiliation></author></analytic><series><title level="j">International Journal of Oncology</title><idno type="ISSN">1019-6439</idno><idno type="eISSN">1791-2423</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>Gastric cancer is an important cancer type worldwide, the anti-angiogenic agent BC001 can target the vascular endothelial growth factor receptor 2 (VEGFR2), and significantly suppresses the growth of gastric cancer BGC823 cells <italic>in vitro</italic> and <italic>in vivo</italic>. However, numerous results indicated that antiangiogenic drugs could induce autophagy, and the inhibition of autophagy enhanced the anticancer effects of antiangiogenic agents. In the present study, hydroxychloroquine (HCQ), an inhibitor of autophagy, enhanced the antiproliferative and proapoptotic effects of BC001 <italic>in vitro</italic>. Furthermore, HCQ enhanced the antitumor effects of BC001 on BGC823 xenograft tumors <italic>in vivo</italic>. Of note, BC001 neither induced nor inhibited autophagy. RNA-sequencing results revealed that HCQ regulated autophagy or lysosomal-associated genes, such as tumor protein p53-inducible nuclear protein 1, interleukin (IL)1B, tumor necrosis factor (TNF), Mediterranean fever, ubiquitin specific peptidase 36, IL6, neuraminidase (NEU)1, ATP-binding cassette subfamily A member 1, proprotein convertase subtilisin/kexin type 9, myelin basic protein and NEU3. Importantly, HCQ was determined to affect multiple pathways, including 'negative regulation of endothelial cell proliferation', 'blood vessel remodeling', 'cell surface receptor signaling pathways' and 'notch receptor processing' associated with 'signal transduction', 'cancers' and 'immune system', through regulating C-X-C motif chemokine ligand 8, TNF, IL6, intercellular adhesion molecule 1 and FOS genes. In summary, HCQ was proposed to enhance the anticancer effects of BC001 in gastric cancer via complex mechanisms.</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, Rl" uniqKey="Siegel R">RL Siegel</name></author><author><name sortKey="Torre, La" uniqKey="Torre L">LA Torre</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sharma, Mr" uniqKey="Sharma M">MR Sharma</name></author><author><name sortKey="Joshi, Ss" uniqKey="Joshi S">SS Joshi</name></author><author><name sortKey="Karrison, Tg" uniqKey="Karrison T">TG Karrison</name></author><author><name sortKey="Allen, K" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Int. J. Oncol</journal-id><journal-id journal-id-type="publisher-id">IJO</journal-id><journal-title-group><journal-title>International Journal of Oncology</journal-title></journal-title-group><issn pub-type="ppub">1019-6439</issn><issn pub-type="epub">1791-2423</issn><publisher><publisher-name>D.A. Spandidos</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31268153</article-id><article-id pub-id-type="pmc">6615922</article-id><article-id pub-id-type="doi">10.3892/ijo.2019.4824</article-id><article-id pub-id-type="publisher-id">ijo-55-02-0405</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Hydroxychloroquine enhances the antitumor effects of BC001 in gastric cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref><xref rid="fn1-ijo-55-02-0405" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Linqing</given-names></name><xref ref-type="aff" rid="af2-ijo-55-02-0405">2</xref><xref rid="fn1-ijo-55-02-0405" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Yucheng</given-names></name><xref ref-type="aff" rid="af3-ijo-55-02-0405">3</xref></contrib><contrib contrib-type="author"><name><surname>Ye</surname><given-names>Qiang</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Xiuli</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Jinying</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref></contrib><contrib contrib-type="author"><name><surname>Ye</surname><given-names>Ziqi</given-names></name><xref ref-type="aff" rid="af4-ijo-55-02-0405">4</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="af5-ijo-55-02-0405">5</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Xiaolu</given-names></name><xref ref-type="aff" rid="af5-ijo-55-02-0405">5</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Guobing</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref></contrib><contrib contrib-type="author"><name><surname>Fang</surname><given-names>Qingxia</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref></contrib><contrib contrib-type="author"><name><surname>Xuan</surname><given-names>Zixue</given-names></name><xref ref-type="aff" rid="af1-ijo-55-02-0405">1</xref><xref ref-type="corresp" rid="c1-ijo-55-02-0405"></xref></contrib></contrib-group><aff id="af1-ijo-55-02-0405"><label>1</label>Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014</aff><aff id="af2-ijo-55-02-0405"><label>2</label>Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001</aff><aff id="af3-ijo-55-02-0405"><label>3</label>Department of General Surgery, Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014</aff><aff id="af4-ijo-55-02-0405"><label>4</label>Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003</aff><aff id="af5-ijo-55-02-0405"><label>5</label>Buchang (Beijing) Pharmaceutical R&D Co., Ltd., Beijing 100176, P.R. China</aff><author-notes><corresp id="c1-ijo-55-02-0405">Correspondence to: Professor Zixue Xuan, Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China, E-mail: <email>xuanzixue0222@163.com</email></corresp><fn id="fn1-ijo-55-02-0405" fn-type="equal"><label>*</label><p>Contributed equally</p></fn></author-notes><pub-date pub-type="collection"><month>8</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>12</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>6</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>55</volume><issue>2</issue><fpage>405</fpage><lpage>414</lpage><history><date date-type="received"><day>13</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>11</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>Copyright: © Wang et al.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivs License</ext-link>, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</license-p></license></permissions><abstract><p>Gastric cancer is an important cancer type worldwide, the anti-angiogenic agent BC001 can target the vascular endothelial growth factor receptor 2 (VEGFR2), and significantly suppresses the growth of gastric cancer BGC823 cells <italic>in vitro</italic> and <italic>in vivo</italic>. However, numerous results indicated that antiangiogenic drugs could induce autophagy, and the inhibition of autophagy enhanced the anticancer effects of antiangiogenic agents. In the present study, hydroxychloroquine (HCQ), an inhibitor of autophagy, enhanced the antiproliferative and proapoptotic effects of BC001 <italic>in vitro</italic>. Furthermore, HCQ enhanced the antitumor effects of BC001 on BGC823 xenograft tumors <italic>in vivo</italic>. Of note, BC001 neither induced nor inhibited autophagy. RNA-sequencing results revealed that HCQ regulated autophagy or lysosomal-associated genes, such as tumor protein p53-inducible nuclear protein 1, interleukin (IL)1B, tumor necrosis factor (TNF), Mediterranean fever, ubiquitin specific peptidase 36, IL6, neuraminidase (NEU)1, ATP-binding cassette subfamily A member 1, proprotein convertase subtilisin/kexin type 9, myelin basic protein and NEU3. Importantly, HCQ was determined to affect multiple pathways, including 'negative regulation of endothelial cell proliferation', 'blood vessel remodeling', 'cell surface receptor signaling pathways' and 'notch receptor processing' associated with 'signal transduction', 'cancers' and 'immune system', through regulating C-X-C motif chemokine ligand 8, TNF, IL6, intercellular adhesion molecule 1 and FOS genes. In summary, HCQ was proposed to enhance the anticancer effects of BC001 in gastric cancer via complex mechanisms.</p></abstract><kwd-group><kwd>gastric cancer</kwd><kwd>hydroxychloroquine</kwd><kwd>autophagy</kwd><kwd>antiangiogenic agent</kwd><kwd>RNA-sequencing</kwd><kwd>immune</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 1</label><caption><p>HCQ promotes the antitumor effects of BC001 <italic>in vitro</italic>. (A) HCQ inhibited BGC823 cell viability in a dose-dependent manner using a Cell Counting Kit-8 assay; (B) HCQ enhanced the anti-proliferative effects of BC001 on BGC823 cells as determined with a Real-time cell analyzer System. (C) HCQ promoted the apoptosis of BGC823 cells following BC001 treatment as determined by flow cytometry. (D) Apoptosis ratio of cells treated with HCQ and/or BC001. <sup>***</sup>P<0.001 vs. CK. CK, control group; FITC, fluorescein isothiocyanate; HCQ, hydroxychloroquine; I<sub>max</sub>, maximal inhibitory concentration; IC<sub>50</sub> half-maximal inhibitory concentration.</p></caption><graphic xlink:href="IJO-55-02-0405-g00"></graphic></fig><fig id="f2-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 2</label><caption><p>HCQ enhances the anticancer activity of BC001 <italic>in vivo</italic>. The tumor (A) volume and (B) weight of the different groups. (C) Relative Ki67, cas-pase-3, cle-caspase-3, CD31 expression was determined by immunohistochemical staining. Scale bar: 200 <italic>µ</italic>m; magnification of insert, x3. <sup>*</sup>P<0.05, <sup>**</sup>P<0.01, <sup>***</sup>P<0.001vs. CK. Cle, cleaved; CK, control group.</p></caption><graphic xlink:href="IJO-55-02-0405-g01"></graphic></fig><fig id="f3-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Effects of BC001 and/or HCQ on the expression of Beclin1, LC3 and p62. (A) The expression of Beclin1 and LC3 in BGC823 cells treated with BC001; (B) the expression of p62 in BGC823 cells treated with BC001. (C) The expression of p62 and LC3 in BGC823 cells treated with HCQ and/or BC001. (D) Relative expression levels of p62 in BGC823 cells treated with HCQ and/or BC001; (E) relative expression of LC3 II/I in BGC823 cells treated with HCQ and/or BC001. <sup>***</sup>P<0.001 vs. CK. CK, control group; HCQ, hydroxychloroquine; LC3, microtubule-associated light chain 3.</p></caption><graphic xlink:href="IJO-55-02-0405-g02"></graphic></fig><fig id="f4-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Effects of BC001 and/or HCQ on autophagy. (A) An mCherry-EGFP-LC3 reporter was constructed to observe the stepwise progression of autophagy in BGC823 cells. Scale bar: 10 <italic>µ</italic>m. (B) Alterations in mitochondria and autophagosomes present in the cytoplasm were observed by transmission electron microscopy. The red arrows represent mitochondria or autophagosomes. Scale bar: 1 <italic>µ</italic>m. CK, control group; EGFP, enhanced green fluorescent protein; HCQ, hydroxychloroquine.</p></caption><graphic xlink:href="IJO-55-02-0405-g03"></graphic></fig><fig id="f5-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Transcriptome of HCQ and/or BC001-treated cells was analyzed via RNA-sequencing to identify DEGs. (A) Heatmap of the hierarchical clustering of genes in HCQ and/or BC001-treated cells; (B) 679 upregulated and 601 downregulated DEGs in HCQ-treated cells compared with control cells. (C) A total of 319 upregulated and 479 downregulated DEGs were reported in in HCQ + BC001-treated cells compared with BC001-treated cells; (D) HCQ affected the expression of some autophagy and lysosomal genes. <sup>*</sup> means these genes are the common DEGs. CK, control group; DEGs, differentially expressed genes; HCQ, hydroxychloroquine.</p></caption><graphic xlink:href="IJO-55-02-0405-g04"></graphic></fig><fig id="f6-ijo-55-02-0405" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Investigation of the mechanism underlying the promoting effects of HCQ on the anticancer properties of BC001 in gastric cancer. (A) KEGG pathway enrichment analyses; (B) GO term enrichment. (C) Venn diagrams were established and 16 genes were identified; (D) gene co-expression networks revealed highly interconnected 'hub' genes in HCQ and/or BC001-treated cells. CK, control group; GO, Gene Ontology; HCQ, hydroxychloroquine; KEGG, Kyoto Encyclopedia of Genes and Genomes.</p></caption><graphic xlink:href="IJO-55-02-0405-g05"></graphic></fig><table-wrap id="tI-ijo-55-02-0405" orientation="portrait" position="float"><label>Table I</label><caption><p>Sixteen differentially expressed genes in HCQ and/or BC001-treated BGC823 cells.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Gene</th><th valign="top" align="center" rowspan="1" colspan="1">Log2<xref rid="tfn1-ijo-55-02-0405" ref-type="table-fn">a</xref></th><th valign="top" align="center" rowspan="1" colspan="1">Log2<xref rid="tfn2-ijo-55-02-0405" ref-type="table-fn">b</xref></th><th valign="top" align="center" rowspan="1" colspan="1">Log2<xref rid="tfn3-ijo-55-02-0405" ref-type="table-fn">c</xref></th><th valign="top" align="center" rowspan="1" colspan="1">Log2<xref rid="tfn4-ijo-55-02-0405" ref-type="table-fn">d</xref></th><th valign="top" align="center" rowspan="1" colspan="1">Log2<xref rid="tfn5-ijo-55-02-0405" ref-type="table-fn">e</xref></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">RBM14-RBM4</td><td valign="top" align="center" rowspan="1" colspan="1">−1.626</td><td valign="top" align="center" rowspan="1" colspan="1">−2.868</td><td valign="top" align="center" rowspan="1" colspan="1">−1.134</td><td valign="top" align="center" rowspan="1" colspan="1">1.242</td><td valign="top" align="center" rowspan="1" colspan="1">−1.734</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">CITED2</td><td valign="top" align="center" rowspan="1" colspan="1">1.683</td><td valign="top" align="center" rowspan="1" colspan="1">−1.050</td><td valign="top" align="center" rowspan="1" colspan="1">1.597</td><td valign="top" align="center" rowspan="1" colspan="1">2.733</td><td valign="top" align="center" rowspan="1" colspan="1">−2.647</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">NEU3</td><td valign="top" align="center" rowspan="1" colspan="1">−2.047</td><td valign="top" align="center" rowspan="1" colspan="1">−3.233</td><td valign="top" align="center" rowspan="1" colspan="1">−2.138</td><td valign="top" align="center" rowspan="1" colspan="1">1.185</td><td valign="top" align="center" rowspan="1" colspan="1">−1.095</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">SPINK5</td><td valign="top" align="center" rowspan="1" colspan="1">−1.144</td><td valign="top" align="center" rowspan="1" colspan="1">1.720</td><td valign="top" align="center" rowspan="1" colspan="1">−1.328</td><td valign="top" align="center" rowspan="1" colspan="1">−2.864</td><td valign="top" align="center" rowspan="1" colspan="1">3.048</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">SPRED2</td><td valign="top" align="center" rowspan="1" colspan="1">1.401</td><td valign="top" align="center" rowspan="1" colspan="1">−1.111</td><td valign="top" align="center" rowspan="1" colspan="1">1.370</td><td valign="top" align="center" rowspan="1" colspan="1">2.513</td><td valign="top" align="center" rowspan="1" colspan="1">−2.482</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">FOS</td><td valign="top" align="center" rowspan="1" colspan="1">1.921</td><td valign="top" align="center" rowspan="1" colspan="1">−1.428</td><td valign="top" align="center" rowspan="1" colspan="1">2.193</td><td valign="top" align="center" rowspan="1" colspan="1">3.349</td><td valign="top" align="center" rowspan="1" colspan="1">−3.621</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">ADGRD1</td><td valign="top" align="center" rowspan="1" colspan="1">1.814</td><td valign="top" align="center" rowspan="1" colspan="1">−1.122</td><td valign="top" align="center" rowspan="1" colspan="1">1.543</td><td valign="top" align="center" rowspan="1" colspan="1">2.936</td><td valign="top" align="center" rowspan="1" colspan="1">−2.665</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">SCHIP1</td><td valign="top" align="center" rowspan="1" colspan="1">2.065</td><td valign="top" align="center" rowspan="1" colspan="1">4.232</td><td valign="top" align="center" rowspan="1" colspan="1">1.699</td><td valign="top" align="center" rowspan="1" colspan="1">−2.167</td><td valign="top" align="center" rowspan="1" colspan="1">2.533</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">IRS1</td><td valign="top" align="center" rowspan="1" colspan="1">1.218</td><td valign="top" align="center" rowspan="1" colspan="1">−1.362</td><td valign="top" align="center" rowspan="1" colspan="1">1.441</td><td valign="top" align="center" rowspan="1" colspan="1">2.580</td><td valign="top" align="center" rowspan="1" colspan="1">−2.802</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">DLL4</td><td valign="top" align="center" rowspan="1" colspan="1">3.233</td><td valign="top" align="center" rowspan="1" colspan="1">−1.080</td><td valign="top" align="center" rowspan="1" colspan="1">3.140</td><td valign="top" align="center" rowspan="1" colspan="1">4.312</td><td valign="top" align="center" rowspan="1" colspan="1">−4.219</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">CYP26B1</td><td valign="top" align="center" rowspan="1" colspan="1">1.737</td><td valign="top" align="center" rowspan="1" colspan="1">−1.158</td><td valign="top" align="center" rowspan="1" colspan="1">1.379</td><td valign="top" align="center" rowspan="1" colspan="1">2.895</td><td valign="top" align="center" rowspan="1" colspan="1">−2.536</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">SHROOM3</td><td valign="top" align="center" rowspan="1" colspan="1">1.296</td><td valign="top" align="center" rowspan="1" colspan="1">−1.236</td><td valign="top" align="center" rowspan="1" colspan="1">1.235</td><td valign="top" align="center" rowspan="1" colspan="1">2.533</td><td valign="top" align="center" rowspan="1" colspan="1">−2.471</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">SPRY4</td><td valign="top" align="center" rowspan="1" colspan="1">3.244</td><td valign="top" align="center" rowspan="1" colspan="1">−1.039</td><td valign="top" align="center" rowspan="1" colspan="1">3.244</td><td valign="top" align="center" rowspan="1" colspan="1">4.284</td><td valign="top" align="center" rowspan="1" colspan="1">−4.284</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">TMEM164</td><td valign="top" align="center" rowspan="1" colspan="1">−1.093</td><td valign="top" align="center" rowspan="1" colspan="1">−2.196</td><td valign="top" align="center" rowspan="1" colspan="1">−1.127</td><td valign="top" align="center" rowspan="1" colspan="1">1.103</td><td valign="top" align="center" rowspan="1" colspan="1">−1.069</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">ZBED3</td><td valign="top" align="center" rowspan="1" colspan="1">−1.788</td><td valign="top" align="center" rowspan="1" colspan="1">−3.010</td><td valign="top" align="center" rowspan="1" colspan="1">−1.804</td><td valign="top" align="center" rowspan="1" colspan="1">1.221</td><td valign="top" align="center" rowspan="1" colspan="1">−1.206</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">EIF4EBP3</td><td valign="top" align="center" rowspan="1" colspan="1">1.567</td><td valign="top" align="center" rowspan="1" colspan="1">5.033</td><td valign="top" align="center" rowspan="1" colspan="1">1.178</td><td valign="top" align="center" rowspan="1" colspan="1">−3.466</td><td valign="top" align="center" rowspan="1" colspan="1">3.855</td></tr></tbody></table><table-wrap-foot><fn id="tfn1-ijo-55-02-0405"><label>a</label><p>Log2 combination vs. CK;</p></fn><fn id="tfn2-ijo-55-02-0405"><label>b</label><p>log2 combination vs. HCQ;</p></fn><fn id="tfn3-ijo-55-02-0405"><label>c</label><p>log2 combination vs. BC001;</p></fn><fn id="tfn4-ijo-55-02-0405"><label>d</label><p>Log2 HCQ vs. CK;</p></fn><fn id="tfn5-ijo-55-02-0405"><label>e</label><p>log2 BC001 vs. HCQ. combination, BC001 + HCQ; HCQ, hydroxychloroquine.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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