The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death
Identifieur interne : 000E00 ( Ncbi/Merge ); précédent : 000D99; suivant : 000E01The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death
Auteurs : I-Lun Hsin ; Ying-Hsiang Chou [Taïwan] ; Wei-Li Hung ; Jiunn-Liang Ko ; Po-Hui Wang [Taïwan]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.
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DOI: 10.3390/cancers12010108
PubMed: 31906234
PubMed Central: 7016694
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death</title><author><name sortKey="Hsin, I Lun" sort="Hsin, I Lun" uniqKey="Hsin I" first="I-Lun" last="Hsin">I-Lun Hsin</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation></author><author><name sortKey="Chou, Ying Hsiang" sort="Chou, Ying Hsiang" uniqKey="Chou Y" first="Ying-Hsiang" last="Chou">Ying-Hsiang Chou</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-12-00108">Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-cancers-12-00108">Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation></author><author><name sortKey="Hung, Wei Li" sort="Hung, Wei Li" uniqKey="Hung W" first="Wei-Li" last="Hung">Wei-Li Hung</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation></author><author><name sortKey="Ko, Jiunn Liang" sort="Ko, Jiunn Liang" uniqKey="Ko J" first="Jiunn-Liang" last="Ko">Jiunn-Liang Ko</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Po Hui" sort="Wang, Po Hui" uniqKey="Wang P" first="Po-Hui" last="Wang">Po-Hui Wang</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cancers-12-00108">Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cancers-12-00108">School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>School of Medicine, Chung Shan Medical University, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af6-cancers-12-00108">Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31906234</idno><idno type="pmc">7016694</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016694</idno><idno type="RBID">PMC:7016694</idno><idno type="doi">10.3390/cancers12010108</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000463</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000463</idno><idno type="wicri:Area/Pmc/Curation">000463</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000463</idno><idno type="wicri:Area/Pmc/Checkpoint">000331</idno><idno 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Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-12-00108">Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-cancers-12-00108">Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation></author><author><name sortKey="Hung, Wei Li" sort="Hung, Wei Li" uniqKey="Hung W" first="Wei-Li" last="Hung">Wei-Li Hung</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation></author><author><name sortKey="Ko, Jiunn Liang" sort="Ko, Jiunn Liang" uniqKey="Ko J" first="Jiunn-Liang" last="Ko">Jiunn-Liang Ko</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Po Hui" sort="Wang, Po Hui" uniqKey="Wang P" first="Po-Hui" last="Wang">Po-Hui Wang</name><affiliation><nlm:aff id="af1-cancers-12-00108">Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cancers-12-00108">Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cancers-12-00108">School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>School of Medicine, Chung Shan Medical University, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af6-cancers-12-00108">Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201</wicri:regionArea><wicri:noRegion>Taichung 40201</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancers</title><idno type="eISSN">2072-6694</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>ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Willis, S N" uniqKey="Willis S">S.N. Willis</name></author><author><name sortKey="Adams, J M" uniqKey="Adams J">J.M. Adams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oltersdorf, T" uniqKey="Oltersdorf T">T. Oltersdorf</name></author><author><name sortKey="Elmore, S W" uniqKey="Elmore S">S.W. Elmore</name></author><author><name sortKey="Shoemaker, A R" uniqKey="Shoemaker A">A.R. Shoemaker</name></author><author><name sortKey="Armstrong, R C" uniqKey="Armstrong R">R.C. Armstrong</name></author><author><name sortKey="Augeri, D J" uniqKey="Augeri D">D.J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id><journal-id journal-id-type="publisher-id">cancers</journal-id><journal-title-group><journal-title>Cancers</journal-title></journal-title-group><issn pub-type="epub">2072-6694</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31906234</article-id><article-id pub-id-type="pmc">7016694</article-id><article-id pub-id-type="doi">10.3390/cancers12010108</article-id><article-id pub-id-type="publisher-id">cancers-12-00108</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hsin</surname><given-names>I-Lun</given-names></name><xref ref-type="aff" rid="af1-cancers-12-00108">1</xref><xref ref-type="author-notes" rid="fn1-cancers-12-00108">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-5888-4302</contrib-id><name><surname>Chou</surname><given-names>Ying-Hsiang</given-names></name><xref ref-type="aff" rid="af1-cancers-12-00108">1</xref><xref ref-type="aff" rid="af2-cancers-12-00108">2</xref><xref ref-type="aff" rid="af3-cancers-12-00108">3</xref><xref ref-type="author-notes" rid="fn1-cancers-12-00108">†</xref></contrib><contrib contrib-type="author"><name><surname>Hung</surname><given-names>Wei-Li</given-names></name><xref ref-type="aff" rid="af1-cancers-12-00108">1</xref></contrib><contrib contrib-type="author"><name><surname>Ko</surname><given-names>Jiunn-Liang</given-names></name><xref ref-type="aff" rid="af1-cancers-12-00108">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Po-Hui</given-names></name><xref ref-type="aff" rid="af1-cancers-12-00108">1</xref><xref ref-type="aff" rid="af4-cancers-12-00108">4</xref><xref ref-type="aff" rid="af5-cancers-12-00108">5</xref><xref ref-type="aff" rid="af6-cancers-12-00108">6</xref><xref rid="c1-cancers-12-00108" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cancers-12-00108"><label>1</label>Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan<email>hideka.chou@gmail.com</email> (Y.-H.C.);<email>ayuatsushi@hotmail.com</email> (W.-L.H.);<email>jlko@csmu.edu.tw</email> (J.-L.K.)</aff><aff id="af2-cancers-12-00108"><label>2</label>Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan</aff><aff id="af3-cancers-12-00108"><label>3</label>Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</aff><aff id="af4-cancers-12-00108"><label>4</label>Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</aff><aff id="af5-cancers-12-00108"><label>5</label>School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan</aff><aff id="af6-cancers-12-00108"><label>6</label>Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan</aff><author-notes><corresp id="c1-cancers-12-00108"><label>*</label>Correspondence: <email>wang082160@gmail.com</email>; Tel.: +886-4-24739595 (ext. 21721); Fax: +886-4-24738493</corresp><fn id="fn1-cancers-12-00108"><label>†</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>31</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>12</volume><issue>1</issue><elocation-id>108</elocation-id><history><date date-type="received"><day>16</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>29</day><month>12</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>ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.</p></abstract><kwd-group><kwd>ABT-737</kwd><kwd>apoptosis</kwd><kwd>arsenic trioxide</kwd><kwd>autophagy</kwd><kwd>uterine cervical cancer</kwd></kwd-group></article-meta></front><floats-group><fig id="cancers-12-00108-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Effects of ABT-737 and As<sub>2</sub>O<sub>3</sub> on cell viability in cervical cancer cells. (<bold>A</bold>) SiHa (5 × 10<sup>3</sup> cells/96 wells) were treated with different concentrations of ABT-737 (0, 1.25, 2.5, 5 μM) and As<sub>2</sub>O<sub>3</sub> (0, 2, 8 μM) for 48 h. (<bold>B</bold>) Caski cells (5 × 10<sup>3</sup> cells/96 wells) were treated with different concentrations of ABT-737 (0, 1.25, 2.5, 5 μM) and As<sub>2</sub>O<sub>3</sub> (0, 2, 8 μM) for 48 h. The data were expressed as mean ± SD. Significant differences were determined by one-way ANOVA. * <italic>p</italic> < 0.001, compared with cells without treatment; # <italic>p</italic> < 0.001, compared with A<sub>s</sub>2O<sub>3</sub> individually treated but no ABT-737 treated cells. (<bold>C</bold>) Combination index of ABT-737 combined with As<sub>2</sub>O<sub>3</sub> on SiHa cancer cells. (<bold>D</bold>) Combination index of ABT-737 combined with As<sub>2</sub>O<sub>3</sub> on Caski cancer cells.</p></caption><graphic xlink:href="cancers-12-00108-g001"></graphic></fig><fig id="cancers-12-00108-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Effects of ABT-737 and As<sub>2</sub>O<sub>3</sub> mediated apoptosis in cervical cancer cells. (<bold>A</bold>) SiHa and Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were co-treated with ABT-737 and As<sub>2</sub>O<sub>3</sub>. The cells were stained with annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) and analyzed by flow cytometry. annexin V-FITC positive (early apoptosis) and annexin V-FITC/PI positive (late apoptosis) were quantified as apoptosis cells. X axis, annexin staining; Y axis, PI staining. (<bold>B</bold>) SiHa and (<bold>C</bold>) Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were co-treated with As<sub>2</sub>O<sub>3</sub> and ABT-737. Cleaved caspase-7 was detected by Western blot. β-actin was as a loading control. The relative ratio of cleaved caspase-7/β-actin is shown.</p></caption><graphic xlink:href="cancers-12-00108-g002"></graphic></fig><fig id="cancers-12-00108-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Effects of ABT-737 combined with As<sub>2</sub>O<sub>3</sub> on mitochondrial membrane potential (ΔΨm) and mitochondrial membrane related proteins. (<bold>A</bold>) SiHa and Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were combined with ABT-737 and As<sub>2</sub>O<sub>3</sub>for 48 h. The living cells were stained with 5,5,6,6′-tetrachloro-1,1,3,3′-tetraethylbenzimi-dazolylcarbocy-anine iodide (JC-1) dye to detect the mitochondrial membrane potential by flow cytometry. (<bold>B</bold>) SiHa and (<bold>C</bold>) Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were co-treated with ABT-737 and As<sub>2</sub>O<sub>3</sub> for 48 h. Voltage–dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT) 1/2/3 were detected by Western blot. β-actin was used as a loading control. The relative ratio of VDAC1/β-actin and ANT1/2/3/β-actin are shown.</p></caption><graphic xlink:href="cancers-12-00108-g003"></graphic></fig><fig id="cancers-12-00108-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Effects of ABT-737 combined with As<sub>2</sub>O<sub>3</sub> on reactive oxygen species (ROS) production in cervical cancer cells. SiHa cells (4 × 10<sup>5</sup> cells/6 cm dish) and Caski (4 × 10<sup>5</sup> cells/6 cm dish) were co-treated with ABT-737 and As<sub>2</sub>O<sub>3</sub> for 8 h. After treatment, the cells were stained with 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) dye to detect the production of ROS by flow cytometry.</p></caption><graphic xlink:href="cancers-12-00108-g004"></graphic></fig><fig id="cancers-12-00108-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>ABT-737 combined with As<sub>2</sub>O<sub>3</sub> altered expression levels of anti-apoptosis proteins and cell cycle regulating protein. (<bold>A</bold>) SiHa and (<bold>B</bold>) Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were combined with ABT-737 and As<sub>2</sub>O<sub>3</sub> for 48 h. Myeloid cell leukemia 1 (Mcl-1), Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak) were detected by Western blot. β-actin was as a loading control. The relative ratio of Mcl-1/β-actin, BAX/β-actin, and Bak/β-actin were shown. (<bold>C</bold>) SiHa and (<bold>D</bold>) Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were combined with ABT-737 and As<sub>2</sub>O<sub>3</sub> for 48 h. Cyclin-dependent kinase 6 (CDK6) and thymidylate synthase (TS) were detected by Western blot. β-actin was as a loading control. The relative ratio of CDK6/β-actin and TS/β-actin are shown.</p></caption><graphic xlink:href="cancers-12-00108-g005"></graphic></fig><fig id="cancers-12-00108-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Effects of ABT-737 and As<sub>2</sub>O<sub>3</sub> on autophagy induction in cervical cancer cells. (<bold>A</bold>) SiHa and (<bold>B</bold>) Caski cells (4 × 10<sup>5</sup> cells/6 cm dish) were co-treated with ABT-737 and As<sub>2</sub>O<sub>3</sub> for 48 h. LC3B was detected by Western blot. β-actin was as a loading control. The relative ratio of LC3B II/LC3B I was shown. (<bold>C</bold>) After pretreatment of 3-MA for 1 h, ABT-737, As<sub>2</sub>O<sub>3</sub>, and chloroquine were treated for 48 h. LC3B and cleaved caspase-7 were detected by Western blot. β-actin was as a loading control. The relative ratio of LC3B-II/LC3B-I and cleaved caspase-7/β-actin are shown.</p></caption><graphic xlink:href="cancers-12-00108-g006"></graphic></fig><fig id="cancers-12-00108-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>A suggested model of ABT-737 combined with As<sub>2</sub>O<sub>3</sub> inducing cell death in SiHa cells.</p></caption><graphic xlink:href="cancers-12-00108-g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Hsin, I Lun" sort="Hsin, I Lun" uniqKey="Hsin I" first="I-Lun" last="Hsin">I-Lun Hsin</name><name sortKey="Hung, Wei Li" sort="Hung, Wei Li" uniqKey="Hung W" first="Wei-Li" last="Hung">Wei-Li Hung</name><name sortKey="Ko, Jiunn Liang" sort="Ko, Jiunn Liang" uniqKey="Ko J" first="Jiunn-Liang" last="Ko">Jiunn-Liang Ko</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Chou, Ying Hsiang" sort="Chou, Ying Hsiang" uniqKey="Chou Y" first="Ying-Hsiang" last="Chou">Ying-Hsiang Chou</name></noRegion><name sortKey="Chou, Ying Hsiang" sort="Chou, Ying Hsiang" uniqKey="Chou Y" first="Ying-Hsiang" last="Chou">Ying-Hsiang Chou</name><name sortKey="Wang, Po Hui" sort="Wang, Po Hui" uniqKey="Wang P" first="Po-Hui" last="Wang">Po-Hui Wang</name><name sortKey="Wang, Po Hui" sort="Wang, Po Hui" uniqKey="Wang P" first="Po-Hui" last="Wang">Po-Hui Wang</name><name sortKey="Wang, Po Hui" sort="Wang, Po Hui" uniqKey="Wang P" first="Po-Hui" last="Wang">Po-Hui Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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