Vitamin D3 potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway
Vitamin D3 potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway
复制标题
DOI：
10.1111/1440-1681.12409
复制
发表时间：
2015-06-01
影响因子：
2.9
通讯作者：
Wu, Yong-Jie
中科院分区：
文献类型：
--
作者：
Li, Hong-Xia;Gao, Jing-Miao;Wu, Yong-Jie
二甲双胍和维生素D-3在许多癌细胞系中都表现出很强的抗增殖作用，包括在人类前列腺癌细胞中。在这里，我们表明，两种药物的组合对DU145人前列腺癌细胞生长的影响比单独使用任何一种药物都要强得多。采用四甲基偶氮唑蓝(MTT)比色法检测细胞增殖。Hoechst 33342染色检测细胞凋亡率。用Western blotting和细胞周期分析来阐明药物之间相互作用的潜在机制。结果表明，在培养的DU145细胞中，维生素D-3与二甲双胍联合应用对细胞增殖和凋亡具有协同作用。其抗肿瘤机制可能涉及改变细胞周期分布，使细胞周期停滞于G1/S期，激活磷酸化AMPK，进而抑制下游mTOR信号通路，下调c-Myc表达，降低抗凋亡蛋白p-Bcl2的水平。综上所述，二甲双胍和维生素D-3协同抑制DU145细胞生长，为雄激素非依赖性前列腺癌的治疗提供了一种很有前景的临床治疗策略。
Metformin and vitamin D-3 both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone. In this research, cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was determined with Hoechst 33342 staining. Western blotting and cell cycle analyses were used to elucidate potential mechanisms of interaction between the drugs. It is shown that in cultured DU145 cells, vitamin D-3 combined with metformin exhibits synergistic effects on cell proliferation and apoptosis. The underlying antitumor mechanisms may involve altered cycle distribution with a G1/S cell cycle arrest, activation of phospho-AMPK with subsequent inhibition of downstream mTOR signalling pathway, down-regulate c-Myc expression, and reducing the level of anti-apoptotic protein p-Bcl-2. In conclusion, metformin and vitamin D-3 synergistically inhibit DU145 cell growth, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.