二甲双胍增强子宫内膜癌顺铂化疗敏感性及其可能机制

Metformin enhances chemosensitivity of endometrial cancer to cisplatin

目的探讨二甲双胍(Met)增强子宫内膜癌顺铂(DDP)化疗敏感性及其可能机制。方法体外培养子宫内膜癌Ishikawa细胞,采用不同浓度的Met和DDP单药或联合用药处理。MTT检测各组细胞的增殖活性,流式细胞术检测两药单用及合用对Ishikawa细胞凋亡和周期的影响,Western blot法检测药物干预后子宫内膜癌细胞内胰岛素生长因子1(IGF-1)和雷帕霉素靶蛋白(mTOR)表达量的变化。结果 Met呈浓度和时间依赖性增强DDP对Ishikawa细胞增殖的抑制(P<0.05)。与Met或DDP单药组比较,联合用药组细胞的凋亡率高(P<0.05),Ishikawa细胞中G0/G1期细胞比例增加,S期细胞比例降低,IGF-1和mTOR蛋白表达水平下降(P<0.05)。结论 Met不仅能对子宫内膜癌细胞的增殖产生抑制作用,同时也可以增强DDP对子宫内膜癌化疗的敏感性,其作用机制可能与Met降低IGF-1和mTOR的表达有关。

Objective To investigate the effect and underlying mechanism of metformin on chemosensitivity of human endometrial carcinoma cells to cisplatin.Methods Human endometrial carcinoma cell line Ishikawa was cultured in vitro and treated with various concentrations of metformin and/or cisplatin.Ishikawa cell proliferation was evaluated by MTT assay and cell cycle was analyzed by PI straining flow cytometry.The expressions of insulin growth factor-1（IGF-1）and mammalian target of rapamycin（mTOR）in Ishikawa cells were detected by Western blot.Results Metformin could significantly enhance the inhibition effect of cisplatin on the proliferation of Ishikawa cells in the dose-and time-dependent manners（P〈0.05）.Compared to cisplatin or metformin alone,combined use of cisplatin and metformin produced higher apoptosis rate and percentage of the cells in G0/G1 stage,decreased the percentage of the cells in S stage,and reduced the expressions of IGF-1and mTOR in Ishikawa cells（P〈0.05）.Conclusion Metformin can inhibit the proliferation of endometrial cancer cells and enhance the sensitivity of cisplatin to endometrial cancer chemotherapy,for which the mechanism might be related to the decreases of IGF-1and mTOR expressions.