Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer
Identifieur interne : 000830 ( Ncbi/Merge ); précédent : 000829; suivant : 000831Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer
Auteurs : Xinwen Liao [République populaire de Chine] ; Yaqiong Fan [République populaire de Chine] ; Jihuan Hou [République populaire de Chine] ; Xiong Chen [République populaire de Chine] ; Xiaolin Xu [République populaire de Chine] ; Yifan Yang [République populaire de Chine] ; Jinying Shen [République populaire de Chine] ; Panying Mi [République populaire de Chine] ; Xiaohua Huang [République populaire de Chine] ; Wenqing Zhang [République populaire de Chine] ; Hanwei Cao [République populaire de Chine] ; Xiaoting Hong [République populaire de Chine] ; Tianhui Hu [République populaire de Chine] ; Yan-Yan Zhan [République populaire de Chine]Source :
- Journal of Cancer [ 1837-9664 ] ; 2019.
Abstract
Chaetocin, a natural product extracted from Chaetomium species, possesses anticancer effects in several kinds of tumors. However, it remains unclear whether the potential indication for chaetocin could also include human gastric cancer. We found here that chaetocin induced caspase-dependent and -independent apoptosis in human gastric cancer cell lines, which greatly depended on BID-mediated AIF translocation. Despite not increasing the intercellular ROS levels in gastric cancer cells, chaetocin did cause a reduction in mitochondrial membrane potential probably through its regulation on the expression of Bcl-2 and BAX. Chaetocin could also induce autophagy in gastric cancer cells; blocking autophagy by chloroquine enhanced the cytotoxicity of chaetocin. Chaetocin was further found to suppress the growth of gastric cancer xenograft in nude mice. Therefore, our study provides first evidence that chaetocin has an anticancer efficacy against gastric cancer and the combined use of chaetocin with autophagy inhibitors may enhance the therapeutic effect for gastric cancer. As chronic and exorbitant ROS levels instigate drug resistance, chaetocin, which eradicates gastric cancer cells without increasing ROS levels, may initiate a new line of non-ROS-mediated anti-tumor strategy.
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DOI: 10.7150/jca.32803
PubMed: 31333785
PubMed Central: 6636309
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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Fan, Yaqiong" sort="Fan, Yaqiong" uniqKey="Fan Y" first="Yaqiong" last="Fan">Yaqiong Fan</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Hou, Jihuan" sort="Hou, Jihuan" uniqKey="Hou J" first="Jihuan" last="Hou">Jihuan Hou</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Xiong" sort="Chen, Xiong" uniqKey="Chen X" first="Xiong" last="Chen">Xiong Chen</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Xu, Xiaolin" sort="Xu, Xiaolin" uniqKey="Xu X" first="Xiaolin" last="Xu">Xiaolin Xu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Yifan" sort="Yang, Yifan" uniqKey="Yang Y" first="Yifan" last="Yang">Yifan Yang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Shen, Jinying" sort="Shen, Jinying" uniqKey="Shen J" first="Jinying" last="Shen">Jinying Shen</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Mi, Panying" sort="Mi, Panying" uniqKey="Mi P" first="Panying" last="Mi">Panying Mi</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Xiaohua" sort="Huang, Xiaohua" uniqKey="Huang X" first="Xiaohua" last="Huang">Xiaohua Huang</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Wenqing" sort="Zhang, Wenqing" uniqKey="Zhang W" first="Wenqing" last="Zhang">Wenqing Zhang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Cao, Hanwei" sort="Cao, Hanwei" uniqKey="Cao H" first="Hanwei" last="Cao">Hanwei Cao</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Hong, Xiaoting" sort="Hong, Xiaoting" uniqKey="Hong X" first="Xiaoting" last="Hong">Xiaoting Hong</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Tianhui" sort="Hu, Tianhui" uniqKey="Hu T" first="Tianhui" last="Hu">Tianhui Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author><author><name sortKey="Zhan, Yan Yan" sort="Zhan, Yan Yan" uniqKey="Zhan Y" first="Yan-Yan" last="Zhan">Yan-Yan Zhan</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian</wicri:regionArea><wicri:noRegion>Fujian</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of Cancer</title><idno type="eISSN">1837-9664</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>Chaetocin, a natural product extracted from Chaetomium species, possesses anticancer effects in several kinds of tumors. However, it remains unclear whether the potential indication for chaetocin could also include human gastric cancer. We found here that chaetocin induced caspase-dependent and -independent apoptosis in human gastric cancer cell lines, which greatly depended on BID-mediated AIF translocation. Despite not increasing the intercellular ROS levels in gastric cancer cells, chaetocin did cause a reduction in mitochondrial membrane potential probably through its regulation on the expression of Bcl-2 and BAX. Chaetocin could also induce autophagy in gastric cancer cells; blocking autophagy by chloroquine enhanced the cytotoxicity of chaetocin. Chaetocin was further found to suppress the growth of gastric cancer xenograft in nude mice. Therefore, our study provides first evidence that chaetocin has an anticancer efficacy against gastric cancer and the combined use of chaetocin with autophagy inhibitors may enhance the therapeutic effect for gastric cancer. As chronic and exorbitant ROS levels instigate drug resistance, chaetocin, which eradicates gastric cancer cells without increasing ROS levels, may initiate a new line of non-ROS-mediated anti-tumor strategy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferro, A" uniqKey="Ferro A">A Ferro</name></author><author><name sortKey="Peleteiro, B" uniqKey="Peleteiro B">B Peleteiro</name></author><author><name sortKey="Malvezzi, M" uniqKey="Malvezzi M">M Malvezzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Macdonald, Js" uniqKey="Macdonald J">JS Macdonald</name></author><author><name sortKey="Smalley, Sr" uniqKey="Smalley S">SR Smalley</name></author><author><name sortKey="Benedetti, J" uniqKey="Benedetti J">J Benedetti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Angelis, R" uniqKey="De Angelis R">R De Angelis</name></author><author><name sortKey="Sant, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Cancer</journal-id><journal-id journal-id-type="iso-abbrev">J Cancer</journal-id><journal-id journal-id-type="publisher-id">jca</journal-id><journal-title-group><journal-title>Journal of Cancer</journal-title></journal-title-group><issn pub-type="epub">1837-9664</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31333785</article-id><article-id pub-id-type="pmc">6636309</article-id><article-id pub-id-type="doi">10.7150/jca.32803</article-id><article-id pub-id-type="publisher-id">jcav10p3678</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liao</surname><given-names>Xinwen</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Fan</surname><given-names>Yaqiong</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Hou</surname><given-names>Jihuan</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Xiong</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Xiaolin</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Yifan</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shen</surname><given-names>Jinying</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mi</surname><given-names>Panying</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Xiaohua</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Wenqing</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Hanwei</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hong</surname><given-names>Xiaoting</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Tianhui</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhan</surname><given-names>Yan-yan</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</aff><aff id="A2"><label>2</label>Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian, P.R. China</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding author: Y.-Y.Z. (Email: <email>yyzhan@xmu.edu.cn</email>, Tel: +86-592-2188223)</corresp><fn fn-type="equal" id="FNA_number"><p><sup>#</sup>These authors contribute equally to this work.</p></fn><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>9</day><month>6</month><year>2019</year></pub-date><volume>10</volume><issue>16</issue><fpage>3678</fpage><lpage>3690</lpage><history><date date-type="received"><day>4</day><month>1</month><year>2019</year></date><date date-type="accepted"><day>14</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© Ivyspring International Publisher</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 Creative Commons Attribution (CC BY-NC) license (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/">https://creativecommons.org/licenses/by-nc/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><p>Chaetocin, a natural product extracted from Chaetomium species, possesses anticancer effects in several kinds of tumors. However, it remains unclear whether the potential indication for chaetocin could also include human gastric cancer. We found here that chaetocin induced caspase-dependent and -independent apoptosis in human gastric cancer cell lines, which greatly depended on BID-mediated AIF translocation. Despite not increasing the intercellular ROS levels in gastric cancer cells, chaetocin did cause a reduction in mitochondrial membrane potential probably through its regulation on the expression of Bcl-2 and BAX. Chaetocin could also induce autophagy in gastric cancer cells; blocking autophagy by chloroquine enhanced the cytotoxicity of chaetocin. Chaetocin was further found to suppress the growth of gastric cancer xenograft in nude mice. Therefore, our study provides first evidence that chaetocin has an anticancer efficacy against gastric cancer and the combined use of chaetocin with autophagy inhibitors may enhance the therapeutic effect for gastric cancer. As chronic and exorbitant ROS levels instigate drug resistance, chaetocin, which eradicates gastric cancer cells without increasing ROS levels, may initiate a new line of non-ROS-mediated anti-tumor strategy.</p></abstract><kwd-group><kwd>Chaetocin</kwd><kwd>gastric cancer</kwd><kwd>apoptosis</kwd><kwd>AIF</kwd><kwd>non-ROS-mediated</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Fig 1</label><caption><p><bold> Chaetocin induced cell death in human gastric cancer cells.</bold> (<bold>A-B</bold>) Dose- and time-dependent cell death was induced by chaetocin in gastric cancer cells. Three human gastric cancer cell lines (AGS, HGC-27 and NCI-N87) were treated with different concentrations of chaetocin for 24 h (<bold>A</bold>), or with chaetocin at the concentration of IC<sub>50</sub> (in figure <bold>A</bold>) for different time periods (0, 12, 24, 36, 48 h) (<bold>B</bold>), and then subjected to MTT assay for the determination of cell viability. (<bold>C</bold>) Chaetocin-induced cell apoptosis was examined by Annexin V-FITC/PI staining and flow cytometry. (<bold>D</bold>) Chaetocin-induced apoptosis was detected by morphological observation. AGS and HGC-27 cells were treated with chaetocin at the concentration of IC<sub>50</sub> for 24 h in figures <bold>C</bold>-<bold>D</bold>. Typical apoptotic nuclei were indicated by white arrows. (<bold>E</bold>) Cleavage of apoptosis-related proteins was analyzed by western blotting. AGS and HGC-27 cells were treated with different concentrations of chaetocin for 24 h. (<bold>F</bold>) Effects of Z-VAD-FMK and necrostatin-1 on chaetocin-induced cell death. AGS and HGC-27 cells were pretreated with Z-VAD-FMK (30 μM, 2 h) or necrostatin-1 (20 μM, 2 h) before chaetocin treatment (at the concentration of IC<sub>50</sub>, 24 h), and the cell viability was analyzed by MTT assay. All data are presented as means ± SEM. The basal level of cell viability was normalized to 1. ***<italic>P</italic> < 0.001, ns nonsignificant.</p></caption><graphic xlink:href="jcav10p3678g001"></graphic></fig><fig id="F2" position="float"><label>Fig 2</label><caption><p><bold> AIF was essential for chaetocin to induce cell death in gastric cancer cells.</bold> (<bold>A</bold>-<bold>B</bold>) AIF knockdown efficiency in AGS and HGC-27 cells was examined by western blotting (<bold>A</bold>) and real-time PCR (<bold>B</bold>). (<bold>C</bold>-<bold>D</bold>) Knocking down AIF attenuated cytotoxicity of chaetocin in AGS and HGC-27 cells. Cell sublines, including shCtrl, shAIF-1 and shAIF-2, were treated with chaetocin at the concentration of IC<sub>50</sub> for 24 h, and then subjected to MTT assay (<bold>C</bold>), or PI staining and flow cytometry (<bold>D</bold>). Data were presented as the mean ± SEM. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001, ns nonsignificant.</p></caption><graphic xlink:href="jcav10p3678g002"></graphic></fig><fig id="F3" position="float"><label>Fig 3</label><caption><p><bold> BID mediated the cell death induced by chaetocin via promoting AIF translocation.</bold> (<bold>A</bold>-<bold>B</bold>) Chaetocin induced the translocation of AIF from cytoplasm to the nucleus in gastric cancer cells as indicated by immunostaining (<bold>C</bold>) and isolation of nuclear and cytoplasmic fractions (<bold>D</bold>) assays. AGS and HGC-27 cells were treated with chaetocin at the concentration of IC<sub>50</sub> for 24 h. Cytoplasmic and nuclear fractions were prepared for western blotting analysis using anti-AIF, anti-β-tubulin (cytosolic marker), and anti-Lamin B (nuclear marker) antibodies. C: cytoplasm; N: nuclei. (<bold>C</bold>-<bold>D</bold>) BID inhibitor BI-6C9 suppressed AIF translocation and cell death induced by chaetocin in AGS and HGC-27 cells. Cells were pretreated with BI-6C9 (10 μM) for 2 h, and then treated with chaetocin at the concentration of IC<sub>50</sub> for 24 h, followed by immunostaining (<bold>C</bold>) and PI staining and flow cytometry (<bold>D</bold>) analyses. Data were presented as the mean ± SEM. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001.</p></caption><graphic xlink:href="jcav10p3678g003"></graphic></fig><fig id="F4" position="float"><label>Fig 4</label><caption><p><bold> Chaetocin reduced mitochondrial membrane potential without increasing intercellular ROS levels.</bold> (<bold>A</bold>-<bold>B</bold>) Effect of chaetocin on the intercellular ROS levels of AGS, HGC-27 and HeLa cells. Cells were treated with different doses of chaetocin as indicated for 24 h (<bold>A</bold>) or with chaetocin at the at the concentration of IC<sub>50</sub> for different time periods (0, 2, 4, 6, 8, 10, 12 h) (<bold>B</bold>). ROS levels were then detected by flow cytometry. (<bold>C</bold>) IC<sub>50</sub> of chaetocin on cell viability of HeLa cells. Cells were treated with different concentrations of chaetocin for 24 h, and the cell viability was determined by MTT assay. (<bold>D</bold>) Effect of ROS scavenger NAC on chaetocin-induced cell death. AGS and HGC-27 cells were pretreated with NAC (10 μM) for 2 h before chaetocin treatment at the concentration of IC<sub>50</sub> for 24 h, and then subjected to MTT assay. (<bold>E</bold>) Chaetocin decreased the mitochondrial membrane potential of AGS and HGC-27 cells. Cells were collected after chaetocin treatment at the concentration of IC<sub>50</sub> for 24 h and the mitochondrial membrane potential was measured by JC-1 staining and flow cytometry. (<bold>F</bold>) Expression levels of BAX and Bcl-2 proteins after chaetocin treatment (24 h) were determined by western blotting. Data were presented as the mean ± SEM. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001, ns nonsignificant.</p></caption><graphic xlink:href="jcav10p3678g004"></graphic></fig><fig id="F5" position="float"><label>Fig 5</label><caption><p><bold> Suppression of autophagy enhanced cytotoxicity of chaetocin in gastric cancer cells.</bold> (<bold>A</bold>) Effect of chaetocin on the expression of autophagy markers was analyzed by western blotting. Cells were treated with different concentrations of chaetocin for 24 h. (<bold>B-C</bold>) Chaetocin-induced autophagy was examined by acridine orange staining (<bold>B</bold>) and GFP-LC3 puncta (<bold>C</bold>) after treatment at the concentration of IC<sub>50</sub> for 24 h. (<bold>D</bold>-<bold>E</bold>) Chloroquine (CQ) strengthened chaetocin's effects on cell death and the cleavage of caspase-3 and PARP. AGS and HGC-27 cells were pretreated with CQ (10 μM) for 2 h before chaetocin treatment at the concentration of IC<sub>50</sub> for 24 h, and then subjected to western blotting (<bold>D</bold>) or MTT assay (<bold>E</bold>). Data were presented as the mean ± SEM. *<italic>P</italic> < 0.05, ***<italic>P</italic> < 0.001, ns nonsignificant.</p></caption><graphic xlink:href="jcav10p3678g005"></graphic></fig><fig id="F6" position="float"><label>Fig 6</label><caption><p><bold> Chaetocin inhibited growth of HGC-27 xenografts in nude mice.</bold> (<bold>A</bold>) Weight of tumor samples from the nude mice treated with vehicle or chaetocin. HGC-27 cells were injected subcutaneously into the right armpit of nude mice. One week later, paired mice with equal tumor volume were separately arranged into the chaetocin group (n = 6) and the vehicle group (n = 6), and then injected intraperitoneally (i.p.) daily with chaetocin (0.5 mg/kg) or vehicle for 10 days. Data were presented as the mean ± SEM. *<italic>P</italic> < 0.05 <italic>vs</italic> control (unpaired <italic>t</italic>-test). (<bold>B</bold>) Proposed working model of chaetocin in human gastric cancer cells.</p></caption><graphic xlink:href="jcav10p3678g006"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Liao, Xinwen" sort="Liao, Xinwen" uniqKey="Liao X" first="Xinwen" last="Liao">Xinwen Liao</name></noRegion><name sortKey="Cao, Hanwei" sort="Cao, Hanwei" uniqKey="Cao H" first="Hanwei" last="Cao">Hanwei Cao</name><name sortKey="Chen, Xiong" sort="Chen, Xiong" uniqKey="Chen X" first="Xiong" last="Chen">Xiong Chen</name><name sortKey="Fan, Yaqiong" sort="Fan, Yaqiong" uniqKey="Fan Y" first="Yaqiong" last="Fan">Yaqiong Fan</name><name sortKey="Hong, Xiaoting" sort="Hong, Xiaoting" uniqKey="Hong X" first="Xiaoting" last="Hong">Xiaoting Hong</name><name sortKey="Hou, Jihuan" sort="Hou, Jihuan" uniqKey="Hou J" first="Jihuan" last="Hou">Jihuan Hou</name><name sortKey="Hu, Tianhui" sort="Hu, Tianhui" uniqKey="Hu T" first="Tianhui" last="Hu">Tianhui Hu</name><name sortKey="Huang, Xiaohua" sort="Huang, Xiaohua" uniqKey="Huang X" first="Xiaohua" last="Huang">Xiaohua Huang</name><name sortKey="Mi, Panying" sort="Mi, Panying" uniqKey="Mi P" first="Panying" last="Mi">Panying Mi</name><name sortKey="Shen, Jinying" sort="Shen, Jinying" uniqKey="Shen J" first="Jinying" last="Shen">Jinying Shen</name><name sortKey="Xu, Xiaolin" sort="Xu, Xiaolin" uniqKey="Xu X" first="Xiaolin" last="Xu">Xiaolin Xu</name><name sortKey="Yang, Yifan" sort="Yang, Yifan" uniqKey="Yang Y" first="Yifan" last="Yang">Yifan Yang</name><name sortKey="Zhan, Yan Yan" sort="Zhan, Yan Yan" uniqKey="Zhan Y" first="Yan-Yan" last="Zhan">Yan-Yan Zhan</name><name sortKey="Zhang, Wenqing" sort="Zhang, Wenqing" uniqKey="Zhang W" first="Wenqing" last="Zhang">Wenqing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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