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目的探讨DNA甲基转移酶抑制剂5-aza-2’-deoxycytidine(DAC)与顺铂(CDDP)在前列腺癌细胞中的协同抑制作用。方法采用WST-1法研究DAC和CDDP对4种前列腺癌细胞株的毒性作用,Isobolographic分析检验二者的协同作用。应用流式细胞仪分析联合作用在细胞凋亡诱导和细胞周期捕获中的作用,通过caspase活性和PCNA蛋白表达研究DAC和CDDP在前列腺癌中的协同作用机制。结果DAC能够明显增加前列腺癌细胞对CDDP的敏感性,在所有前列腺癌细胞株中DAC和CDDP均具有协同作用。DAC可诱导G2/M期细胞周期捕获,而CDDP通过诱导凋亡(subG1期)和G2/M期捕获两方面抑制细胞生长。DAC可增强CDDP介导的caspase活性升高和PCNA表达的下调,导致subG1期和G2/M期细胞的增加。结论DAC和CDDP在雄激素依赖和非依赖性前列腺癌细胞株中均具有协同作用,二者联合可改善前列腺癌预后,值得临床推广。
Objective To investigate the synergistic inhibition of DNA methyltransferase 5-aza-2’-deoxycytidine (DAC) and cisplatin (CDDP) in prostate cancer cells. Methods WST-1 method was used to study the toxic effects of DAC and CDDP on four kinds of prostate cancer cell lines. Isobolographic analysis was used to examine the synergistic effect between the two. The role of combined effects in apoptosis induction and cell cycle arrest was analyzed by flow cytometry. The synergistic mechanism of DAC and CDDP in prostate cancer was investigated by caspase activity and PCNA protein expression. Results DAC can significantly increase the sensitivity of prostate cancer cells to CDDP, and synergism exists between DAC and CDDP in all prostate cancer cell lines. DACs induce G2 / M phase cell cycle arrest, while CDDPs suppress cell growth both in apoptosis (subG1 phase) and G2 / M phase arrest. DAC enhanced CDDP-mediated caspase activity and downregulation of PCNA expression, resulting in an increase of subG1 and G2 / M phase cells. Conclusions Both DAC and CDDP have a synergistic effect in androgen-dependent and independent prostate cancer cell lines. The combination of both can improve the prognosis of prostate cancer and deserve clinical promotion.