Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell lines in vitro and in vivo
Identifieur interne : 000394 ( Pmc/Checkpoint ); précédent : 000393; suivant : 000395Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell lines in vitro and in vivo
Auteurs : Tianze Liu [République populaire de Chine] ; Lizi Jin [République populaire de Chine] ; Wenjing Lu [République populaire de Chine] ; Hairun Gan ; Zhidong Lin [République populaire de Chine] ; Miao Chen [République populaire de Chine] ; Jiani Liu [République populaire de Chine] ; Fan Zhang [République populaire de Chine] ; Siyang Wang [République populaire de Chine] ; Hongyu Zhang [République populaire de Chine] ; Wuguo Deng [République populaire de Chine] ; Hongtao Chen [République populaire de Chine]Source :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Abstract
Recent Clinical trials of administration of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with standard first-line chemotherapy have failed to improve survival in patients with advanced NSCLC, However, the sequential treatment with EGFR-TKIs and chemotherapy is expected to improve survival of NSCLC. The aim of this study is to test the antiproliferative effect of pemetrexed combined with icotinib in different sequences on non-small cell lung cancer (NSCLC) cell lines to determine the optimal combination schedule, and subsequently elaborated the potential mechanisms.
Six human lung cancer cell lines with wild-type or mutant EGFR gene were exposed to pemetrexed and icotinib combined in different sequences. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation assay; cell cycle and apoptosis were evaluated by flow cytometry; cell migration and invasion were measured by wound healing and transwell invasion assays respectively; protein expression was by detected by Western blot.
The growth inhibition effect of pemetrexed combined with icotinib on NSCLC cells were schedule-dependent in vitro
Sequential treatment of NSCLC cells with pemetrexed followed by icotinib had powerful antiproliferative effect, and it could become a novel effective combination therapy for NSCLC patients.
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DOI: 10.1186/s13046-019-1133-z
PubMed: 30953548
PubMed Central: 6451286
Affiliations:
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wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Deng, Wuguo" sort="Deng, Wuguo" uniqKey="Deng W" first="Wuguo" last="Deng">Wuguo Deng</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 6191</institution-id><institution-id institution-id-type="GRID">grid.488530.2</institution-id><institution>State Key Laboratory of Oncology in South China,</institution><institution>Sun Yat-sen University Cancer Center,</institution></institution-wrap>Guangzhou, 510060 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Hongtao" sort="Chen, Hongtao" uniqKey="Chen H" first="Hongtao" last="Chen">Hongtao Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Clinical Laboratory,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30953548</idno><idno type="pmc">6451286</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451286</idno><idno type="RBID">PMC:6451286</idno><idno type="doi">10.1186/s13046-019-1133-z</idno><date 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Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 6191</institution-id><institution-id institution-id-type="GRID">grid.488530.2</institution-id><institution>State Key Laboratory of Oncology in South China,</institution><institution>Sun Yat-sen University Cancer Center,</institution></institution-wrap>Guangzhou, 510060 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangzhou</wicri:regionArea></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Guangdong Provincial Engineering Research Center of Molecular Imaging,</institution><institution>The Fifth Affiliated Hospital, Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 Guangdong Province China</nlm:aff><wicri:noCountry code="subfield">519000 Guangdong Province China</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Center for Interventional Medicine,</institution><institution>The Fifth Affiliated Hospital, Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 Guangdong Province China</nlm:aff><wicri:noCountry code="subfield">519000 Guangdong Province China</wicri:noCountry></affiliation></author><author><name sortKey="Jin, Lizi" sort="Jin, Lizi" uniqKey="Jin L" first="Lizi" last="Jin">Lizi Jin</name><affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Cardiology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Wenjing" sort="Lu, Wenjing" uniqKey="Lu W" first="Wenjing" last="Lu">Wenjing Lu</name><affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Cardiology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Gan, Hairun" sort="Gan, Hairun" uniqKey="Gan H" first="Hairun" last="Gan">Hairun Gan</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Center for Interventional Medicine,</institution><institution>The Fifth Affiliated Hospital, Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 Guangdong Province China</nlm:aff><wicri:noCountry code="subfield">519000 Guangdong Province China</wicri:noCountry></affiliation></author><author><name sortKey="Lin, Zhidong" sort="Lin, Zhidong" uniqKey="Lin Z" first="Zhidong" last="Lin">Zhidong Lin</name><affiliation wicri:level="1"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of General Surgery,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-Sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Miao" sort="Chen, Miao" uniqKey="Chen M" first="Miao" last="Chen">Miao Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 6191</institution-id><institution-id institution-id-type="GRID">grid.488530.2</institution-id><institution>State Key Laboratory of Oncology in South China,</institution><institution>Sun Yat-sen University Cancer Center,</institution></institution-wrap>Guangzhou, 510060 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Jiani" sort="Liu, Jiani" uniqKey="Liu J" first="Jiani" last="Liu">Jiani Liu</name><affiliation wicri:level="1"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Radiation Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Fan" sort="Zhang, Fan" uniqKey="Zhang F" first="Fan" last="Zhang">Fan Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Radiation Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Siyang" sort="Wang, Siyang" uniqKey="Wang S" first="Siyang" last="Wang">Siyang Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Radiation Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Hongyu" sort="Zhang, Hongyu" uniqKey="Zhang H" first="Hongyu" last="Zhang">Hongyu Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author><author><name sortKey="Deng, Wuguo" sort="Deng, Wuguo" uniqKey="Deng W" first="Wuguo" last="Deng">Wuguo Deng</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 6191</institution-id><institution-id institution-id-type="GRID">grid.488530.2</institution-id><institution>State Key Laboratory of Oncology in South China,</institution><institution>Sun Yat-sen University Cancer Center,</institution></institution-wrap>Guangzhou, 510060 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Hongtao" sort="Chen, Hongtao" uniqKey="Chen H" first="Hongtao" last="Chen">Hongtao Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Clinical Laboratory,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhuhai</wicri:regionArea></affiliation></author></analytic><series><title level="j">Journal of Experimental & Clinical Cancer Research : CR</title><idno type="ISSN">0392-9078</idno><idno type="eISSN">1756-9966</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">Recent Clinical trials of administration of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with standard first-line chemotherapy have failed to improve survival in patients with advanced NSCLC, However, the sequential treatment with EGFR-TKIs and chemotherapy is expected to improve survival of NSCLC. The aim of this study is to test the antiproliferative effect of pemetrexed combined with icotinib in different sequences on non-small cell lung cancer (NSCLC) cell lines to determine the optimal combination schedule, and subsequently elaborated the potential mechanisms.</p></sec><sec><title>Methods</title><p id="Par2">Six human lung cancer cell lines with wild-type or mutant EGFR gene were exposed to pemetrexed and icotinib combined in different sequences. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation assay; cell cycle and apoptosis were evaluated by flow cytometry; cell migration and invasion were measured by wound healing and transwell invasion assays respectively; protein expression was by detected by Western blot.</p></sec><sec><title>Results</title><p id="Par3">The growth inhibition effect of pemetrexed combined with icotinib on NSCLC cells were schedule-dependent in vitro <italic>and</italic> in vivo. Treatment with pemetrexed followed by icotinib (P-I) had significantly stronger anticancer ability than treatment with icotinib followed by pemetrexed (I-P) and concomitant treatment with pemetrexed and icotinib (P + I). Cell cycle analysis revealed that pemetrexed blocked cells in S phase, whereas icotinib arrested cells in G1 phase. We also found that icotinib markedly enhanced the pro-apoptotic activity of pemetrexed via cytochrome-C/Caspase/Bcl-2 signaling pathway. In addition, our results showed that pemetrexed alone increased the levels of p-EGFR, p-AKT and p-MAPK, which were inhibited by icotinib. Finally, we showed that the washout period of icotinib was no less than 96 h.</p></sec><sec><title>Conclusions</title><p id="Par4">Sequential treatment of NSCLC cells with pemetrexed followed by icotinib had powerful antiproliferative effect, and it could become a novel effective combination therapy for NSCLC patients.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cao, S" uniqKey="Cao S">S Cao</name></author><author><name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name></author><author><name sortKey="Gao, X" uniqKey="Gao X">X Gao</name></author><author><name sortKey="He, W" uniqKey="He W">W He</name></author><author><name sortKey="Cai, Y" uniqKey="Cai Y">Y Cai</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Xu, R" uniqKey="Xu R">R Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoffman, Pc" uniqKey="Hoffman P">PC 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Exp Clin Cancer Res</journal-id><journal-id journal-id-type="iso-abbrev">J. Exp. Clin. Cancer Res</journal-id><journal-title-group><journal-title>Journal of Experimental & Clinical Cancer Research : CR</journal-title></journal-title-group><issn pub-type="ppub">0392-9078</issn><issn pub-type="epub">1756-9966</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30953548</article-id><article-id pub-id-type="pmc">6451286</article-id><article-id pub-id-type="publisher-id">1133</article-id><article-id pub-id-type="doi">10.1186/s13046-019-1133-z</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell lines in vitro and in vivo</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Liu</surname><given-names>Tianze</given-names></name><address><email>ltz14111183@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Jin</surname><given-names>Lizi</given-names></name><address><email>jinlizizhuhai@126.com</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Lu</surname><given-names>Wenjing</given-names></name><address><email>172626217@qq.com</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Gan</surname><given-names>Hairun</given-names></name><address><email>ganhr1013@163.com</email></address><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Zhidong</given-names></name><address><email>2528894435@qq.com</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Miao</given-names></name><address><email>chenmiao@sysucc.org.cn</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jiani</given-names></name><address><email>iujiani@mail2.sysu.edu.cn</email></address><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Fan</given-names></name><address><email>350332694@qq.com</email></address><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Siyang</given-names></name><address><email>13570608929@163.com</email></address><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Zhang</surname><given-names>Hongyu</given-names></name><address><email>zdwyzhy@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Deng</surname><given-names>Wuguo</given-names></name><address><phone>86 20 87342282</phone><email>dengwg@sysucc.org.cn</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Chen</surname><given-names>Hongtao</given-names></name><address><phone>86 13660537335</phone><email>13926925941@139.com</email></address><xref ref-type="aff" rid="Aff8">8</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 6191</institution-id><institution-id institution-id-type="GRID">grid.488530.2</institution-id><institution>State Key Laboratory of Oncology in South China,</institution><institution>Sun Yat-sen University Cancer Center,</institution></institution-wrap>Guangzhou, 510060 China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Guangdong Provincial Engineering Research Center of Molecular Imaging,</institution><institution>The Fifth Affiliated Hospital, Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 Guangdong Province China</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Center for Interventional Medicine,</institution><institution>The Fifth Affiliated Hospital, Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 Guangdong Province China</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Cardiology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of General Surgery,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-Sen University,</institution></institution-wrap>Zhuhai, China</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Radiation Oncology,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, China</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="GRID">grid.452859.7</institution-id><institution>Department of Clinical Laboratory,</institution><institution>The Fifth Affiliated Hospital of Sun Yat-sen University,</institution></institution-wrap>Zhuhai, 519000 China</aff></contrib-group><pub-date pub-type="epub"><day>5</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>5</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>38</volume><elocation-id>148</elocation-id><history><date date-type="received"><day>12</day><month>10</month><year>2018</year></date><date date-type="accepted"><day>13</day><month>3</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s). 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International 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>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">Recent Clinical trials of administration of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with standard first-line chemotherapy have failed to improve survival in patients with advanced NSCLC, However, the sequential treatment with EGFR-TKIs and chemotherapy is expected to improve survival of NSCLC. The aim of this study is to test the antiproliferative effect of pemetrexed combined with icotinib in different sequences on non-small cell lung cancer (NSCLC) cell lines to determine the optimal combination schedule, and subsequently elaborated the potential mechanisms.</p></sec><sec><title>Methods</title><p id="Par2">Six human lung cancer cell lines with wild-type or mutant EGFR gene were exposed to pemetrexed and icotinib combined in different sequences. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation assay; cell cycle and apoptosis were evaluated by flow cytometry; cell migration and invasion were measured by wound healing and transwell invasion assays respectively; protein expression was by detected by Western blot.</p></sec><sec><title>Results</title><p id="Par3">The growth inhibition effect of pemetrexed combined with icotinib on NSCLC cells were schedule-dependent in vitro <italic>and</italic> in vivo. Treatment with pemetrexed followed by icotinib (P-I) had significantly stronger anticancer ability than treatment with icotinib followed by pemetrexed (I-P) and concomitant treatment with pemetrexed and icotinib (P + I). Cell cycle analysis revealed that pemetrexed blocked cells in S phase, whereas icotinib arrested cells in G1 phase. We also found that icotinib markedly enhanced the pro-apoptotic activity of pemetrexed via cytochrome-C/Caspase/Bcl-2 signaling pathway. In addition, our results showed that pemetrexed alone increased the levels of p-EGFR, p-AKT and p-MAPK, which were inhibited by icotinib. Finally, we showed that the washout period of icotinib was no less than 96 h.</p></sec><sec><title>Conclusions</title><p id="Par4">Sequential treatment of NSCLC cells with pemetrexed followed by icotinib had powerful antiproliferative effect, and it could become a novel effective combination therapy for NSCLC patients.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Icotinib</kwd><kwd>Lung cancer</kwd><kwd>EGFR mutation</kwd><kwd>Synergy</kwd><kwd>Washout period</kwd></kwd-group><funding-group><award-group><funding-source><institution>Scientific-Technologic Foundation of GuangDong Province</institution></funding-source><award-id>2010B031600231</award-id><principal-award-recipient><name><surname>Zhang</surname><given-names>Hongyu</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81772925</award-id><award-id>81802936</award-id><principal-award-recipient><name><surname>Liu</surname><given-names>Tianze</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Gan, Hairun" sort="Gan, Hairun" uniqKey="Gan H" first="Hairun" last="Gan">Hairun Gan</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Liu, Tianze" sort="Liu, Tianze" uniqKey="Liu T" first="Tianze" last="Liu">Tianze Liu</name></noRegion><name sortKey="Chen, Hongtao" sort="Chen, Hongtao" uniqKey="Chen H" first="Hongtao" last="Chen">Hongtao Chen</name><name sortKey="Chen, Miao" sort="Chen, Miao" uniqKey="Chen M" first="Miao" last="Chen">Miao Chen</name><name sortKey="Deng, Wuguo" sort="Deng, Wuguo" uniqKey="Deng W" first="Wuguo" last="Deng">Wuguo Deng</name><name sortKey="Jin, Lizi" sort="Jin, Lizi" uniqKey="Jin L" first="Lizi" last="Jin">Lizi Jin</name><name sortKey="Lin, Zhidong" sort="Lin, Zhidong" uniqKey="Lin Z" first="Zhidong" last="Lin">Zhidong Lin</name><name sortKey="Liu, Jiani" sort="Liu, Jiani" uniqKey="Liu J" first="Jiani" last="Liu">Jiani Liu</name><name sortKey="Liu, Tianze" sort="Liu, Tianze" uniqKey="Liu T" first="Tianze" last="Liu">Tianze Liu</name><name sortKey="Lu, Wenjing" sort="Lu, Wenjing" uniqKey="Lu W" first="Wenjing" last="Lu">Wenjing Lu</name><name sortKey="Wang, Siyang" sort="Wang, Siyang" uniqKey="Wang S" first="Siyang" last="Wang">Siyang Wang</name><name sortKey="Zhang, Fan" sort="Zhang, Fan" uniqKey="Zhang F" first="Fan" last="Zhang">Fan Zhang</name><name sortKey="Zhang, Hongyu" sort="Zhang, Hongyu" uniqKey="Zhang H" first="Hongyu" last="Zhang">Hongyu Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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