Wang Zhen-Shi, Huang Hua-Rong, Zhang Lan-Yue, Kim Seungkee, He Yan, Li Dong-Li, Farischon Chelsea, Zhang Kun, Zheng Xi, Du Zhi-Yun, Goodin Susan
Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers.
Biol Pharm Bull. 2017;40(8):1247-1254. doi: 10.1248/bpb.b17-00077.
Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphor-extracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.
二甲双胍是治疗II型糖尿病的常用药物，阿托伐他汀是处方量最多的降胆固醇他汀类药物。本研究调查了二甲双胍和阿托伐他汀联合使用对体外培养的人前列腺癌细胞以及体内异种移植瘤生长的影响及其机制。二甲双胍与阿托伐他汀联合使用对PC-3细胞生长抑制和凋亡的作用比单独使用任一药物更强。该联合用药还能有效抑制细胞迁移和肿瘤球的形成。二甲双胍和阿托伐他汀联合使用对核因子-κB（NF-κB）活性有强大的抑制作用，并使其下游抗凋亡基因Survivin的表达大幅降低。此外，联合用药处理的细胞中磷酸化Akt和磷酸化细胞外信号调节激酶（Erk）1/2的水平显著降低。体内研究表明，单独用二甲双胍或阿托伐他汀治疗严重联合免疫缺陷（SCID）小鼠会导致肿瘤生长受到中度抑制，而联合用药则能强烈抑制肿瘤生长。本研究结果表明，二甲双胍和阿托伐他汀联合使用可能是抑制前列腺癌生长的有效策略，应进行临床评估。
