中文摘要：

目的：探讨组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACi）FK228和哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,m TOR）特异性抑制剂雷帕霉素（rapamycin,Rapa）联合应用对体外人乳腺癌细胞株生长和凋亡的影响及其可能的分子机制。方法：以乳腺癌细胞系MDA-MB-435和MCF-7为研究对象,经不同浓度的FK228和雷帕霉素处理后,磺酰罗丹明B（SRB）比色法检测肿瘤细胞的生长抑制率,计算两药的联合指数;Western blotting检测乳腺癌细胞中凋亡相关蛋白、周期调控蛋白以及核酸相关蛋白的表达;流式细胞术检测细胞周期。结果：（1）FK228或雷帕霉素单独使用时均抑制肿瘤细胞生长,抑制率与时间、剂量呈正相关;当总抑制率为50%~70%时联合指数（CI）值小于1,提示两药联合应用具有协同效应;（2）联合用药后,凋亡蛋白表达较单药使用组明显升高（P〈0.05）;同时,p-Akt蛋白表达下降,活化的caspase-3表达上调;（3）联合用药后,周期调控蛋白表达较单药使用组明显下降（P〈0.05）,细胞周期阻滞在G2/M期;联合用药后出现更为显著的H2AX的磷酸化和H3的乙酰化（P〈0.05）。结论：FK228和雷帕霉素联合给药能协同促进人乳腺癌细胞凋亡和细胞周期阻滞,具有良好的抗肿瘤前景。

英文摘要：

AIM：To investigate the depressant effect of FK228 combined with rapamycin on the human breast cancer cell line MCF-7 and MDA-MB-435.METHODS：FK228, a new histone deacetylase inhibitor, and rapamycin, the specific inhibitor of the mammalian target of rapamycin （ mTOR） protein, were used in the study.MCF-7 cells and MDA-MB-435 cells were exposed to different concentrations of FK228 and rapamycin.The inhibitory rate of cell growth was de-termined by SRB assay.Combination index （ CI） was used to evaluate the interaction between FK228 and rapamycin.The expression of the apoptotic proteins, cycle proteins and nucleic acid proteins were detected by Western blotting.The cell cycle was analyzed by flow cytometry.RESULTS： Both FK228 and rapamycin showed growth inhibitory effects on the breast cancer cell lines in a time-and dose-dependent manner.CI of the 2 drugs was less than 1 when the inhibitory rate of＆amp;nbsp;the cell growth was 50%effective dose （ED50）~ED70, indicating a synergistic effect.The combination therapy of FK228 with rapamycin increased the apoptotic proteins, and induced the down-regulation of phosphorylated Akt and over-expres-sion of caspase-3 compared with a single use of the drugs.The combination therapy of FK228 with rapamycin reduced the cycle proteins, and the cell cycle was arrested in G2/M.The levels of phosphorylated H2AX and acetylated H3 were ob-viously increased after combination therapy.CONCLUSION：The combination therapy of FK228 with rapamycin inhibits the cell proliferation and increases apoptosis with a synergistic effect, which may become a new trend for treating endometri-al cancer.