1.Combination therapy of FK228 with rapamycin synergistically promotes human breast cancer cell apoptosis by DNA damage and cell cycle arrest
Xiaodan PENG ; Menglu ZHU ; Lfen GAO ; Tingting LIU ; Yan LIU ; Yuan OUYANG ; Ruofen LI ; Lifei LIU ; Yi LI ; Xiaoyu LIU ; Xiaohe ZHENG ; Shaoqiang LIN
Chinese Journal of Pathophysiology 2015;33(4):577-584
[ ABSTRACT] 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 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.
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