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The benzaimides chidamide and entinostat are inhibitors of histone deacetylase and have been approved for clinic use. As drug resistance readily occurs in cancer chemotherapy, the characteristics of these drugs were studied in doxorubicin-sensitive and resistant human breast cancer MCF-7 cells. Using a CCK-8 assay for measuring cell proliferation, doxorubicin-resistant cells showed some resistance to chidamide and entinostat, with greater resistance to chidamide. Potentiation of cis-diamine-dichloroplatinum action by entinostat was observed in resistant cells. The accumulation of rhodomine 123, an indirect indicator of ATP-binding cassette B1 (ABCB1)-mediated resistance, was not affected by incubation with chidamide or entinostat, suggesting that neither drug is a substrate for ABCB1. However, ABCB1 expression was significantly increased in resistance cells incubated with a fixed concentration of entinostat. Slowing of the cell cycle at G1 phase and slightly increased cell numbers at G2/M phase was detected by flow cytometry when the cell lines were treated with chidamide or entinostat. Both drugs could induce spherical morphological changes and cleavage of PARP1, an indicater of apoptosis in doxorubicin-sensitive MCF-7 cells, whereas no apoptotic features were observed in resistant cells. These findings show that there is some resistance to chidamide and entinostat in doxorubicin-resistant MCF-7 cells and that this resistance may further oppose apoptosis.
, correspAuthors=Qi-yang HE, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2020 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Qiang GAO, Qi-yang HE), CN=ArticleExt(id=1220655294162584536, articleId=1220655292270953333, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=恩替诺特或西达本胺作用人乳腺癌耐多柔比星的MCF-7细胞的特征, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=
组蛋白去乙酰化酶抑制剂西达本胺和恩替诺特均属苯酰胺类，已经批准在临床应用。鉴于耐药性是癌症化疗中的常见问题，本研究以耐多柔比星的人乳腺癌MCF-7细胞为模型，探讨两药的作用特征。CCK-8增殖实验显示：与敏感细胞相比，耐药细胞对该两药均具有一定的耐药性，尤其是对西达本胺更为明显。恩替诺特可增加顺铂的抑制作用。以罗丹明123滞留作为ATP结合盒转运蛋白1（ATP-binding cassette B1，ABCB1）耐药性的间接指示剂，检测到两药对耐药细胞的罗丹明123的滞留均不明显，说明这些药物不是ABCB1的外排底物。固定浓度的恩替诺特处理耐药细胞，可明显地引起ABCB1蛋白的表达增加。流式细胞术分析细胞周期发现：两药均引起细胞明显的G1期阻滞，轻微地增加G2/M期细胞的数量。细胞凋亡分析发现两药均可引起MCF-7敏感细胞变圆，出现凋亡样形态，凋亡指示蛋白PARP-1出现切割；但对MCF-7耐药细胞均没有诱导凋亡的作用。本研究结果表明：MCF-7耐药细胞对西达本胺或恩替诺特均具有一定的耐药性，抗细胞凋亡可能是其耐药特征之一。
, correspAuthors=何琪杨, authorNote=null, correspAuthorsNote=
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10: 86., articleTitle=Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer, refAbstract=null)], funds=[Fund(id=1220655297731936557, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, awardId=31471150, language=CN, fundingSource=国家自然科学基金面上项目(31471150), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1220655294531683316, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, xref=null, ext=[AuthorCompanyExt(id=1220655294540071925, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, companyId=1220655294531683316, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medical Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1220655294548460534, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, companyId=1220655294531683316, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院, 北京协和医学院医药生物技术研究所, 北京 100050)])], figs=[ArticleFig(id=1220655296393953444, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=EN, label=null, caption=null, figureFileSmall=B7LHFYd3/lKXXwLjgolKSQ==, figureFileBig=yPFGMnsE4yrjBu2qge/TGA==, tableContent=null), ArticleFig(id=1220655296536559794, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=CN, label=Figure 1, caption=
The resistance to CHI or ENT in MCF-7/DOX cells. The cell survival was assayed with CCK-8 method after the cells were treated with DOX (A), VCR (B), ENT (C) and CHI (D) for 96 h. <i>n</i> = 3, $\bar{x} \pm s$. CHI: Chidamide; ENT: Entinostat; DOX: Doxorubicin; VCR: Vincristine , figureFileSmall=B7LHFYd3/lKXXwLjgolKSQ==, figureFileBig=yPFGMnsE4yrjBu2qge/TGA==, tableContent=null), ArticleFig(id=1220655296771440849, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=EN, label=null, caption=null, figureFileSmall=cyG2ph3nzjKPVHnNXB4+RA==, figureFileBig=PWBSu0I7vWrkVf2rubxqxA==, tableContent=null), ArticleFig(id=1220655296859521238, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=CN, label=Figure 2, caption=
The proliferation-inhibitory action of <i>cis</i>-diammine-dichloroplatinum (DDP) potentiated by ENT on MCF-7/DOX cells. The cell survival was determined with Coulter counter method after the cells were treated with ENT or DDP alone, and DDP+ENT for 72 h. The concentrations of ENT used were 0.2 and 0.5 μmol·L<sup>-1</sup>. <i>n</i> = 3, $\bar{x} \pm s$. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=cyG2ph3nzjKPVHnNXB4+RA==, figureFileBig=PWBSu0I7vWrkVf2rubxqxA==, tableContent=null), ArticleFig(id=1220655296981156069, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=EN, label=null, caption=null, figureFileSmall=FylEQtAm4xMNBI6rhWlMaQ==, figureFileBig=biR0zm8oustIg0j1bZw+QQ==, tableContent=null), ArticleFig(id=1220655297081819373, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=CN, label=Figure 3, caption=
Effects of ATP-binding cassette B1 (ABCB1) function by ENT or CHI in MCF-7/DOX resistant cells. A: high expression of ABCB1 was detected by Western blotting in the resistant cells; B: Lower accumulation of rhodamine 123 was determined by flow cytometry in the resistant cells; C: CHI or ENT is not a substrate of ABCB1 using rhodamine 123 accumulaition assay in the resistant cells. i: Control; ii: TET 2 μmol·L<sup>-1</sup>; iii: CHI 50 μmol·L<sup>-1</sup>; iv: CHI 100 μmol·L<sup>-1</sup>; v: ENT 5 μmol·L<sup>-1</sup>; vi: ENT 10 μmol·L<sup>-1</sup>. D: ABCB1 expression was induced by ENT 25 μmol·L<sup>-1</sup> for different time points in the resistant cells. In the figure, "sol" indicates solvent. One of reprentative result from three experiments was shown , figureFileSmall=FylEQtAm4xMNBI6rhWlMaQ==, figureFileBig=biR0zm8oustIg0j1bZw+QQ==, tableContent=null), ArticleFig(id=1220655297169899768, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=EN, label=null, caption=null, figureFileSmall=L7S602D78ZY304y93AgINw==, figureFileBig=hVc/sNCQ/1xjqxRV+18Tog==, tableContent=null), ArticleFig(id=1220655297266368773, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=CN, label=Figure 4, caption=
Effects of CHI (A) and ENT (B) on the distrabution of cell cyle. The assay was determined by flow cytometer. One of presentive result from two experiments is shown , figureFileSmall=L7S602D78ZY304y93AgINw==, figureFileBig=hVc/sNCQ/1xjqxRV+18Tog==, tableContent=null), ArticleFig(id=1220655297354449169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=EN, label=null, caption=null, figureFileSmall=WtceC8cFfhGYEBfz+xmypQ==, figureFileBig=3sXU7KjDbV/6YTNLjpu5bg==, tableContent=null), ArticleFig(id=1220655297564164376, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292270953333, language=CN, label=Figure 5, caption=
Effects of apoptosis by CHI or ENT on the sensitive and resistant MCF-7 cells. A: The morphological changes of both cell lines after exposure to CHI or ENT for 24 h. Magnification 100×; B: The changes of apoptosis-related proteins after the cells were treated with CHI; C: The changes of apoptosis-related proteins after the cells were treated with ENT. In figure B and C, "*" indicates a cleavage fragment of PARP-1. 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