Mefformin Enhances The Anti-Prostate Cancer Activity Of Abiraterone And Enzalutamide

The standard treatment for advanced castration sensitive prostate cancer (CSPC) is androgen deprivation therapy (ADT), generally in the form of suppression of gonadally produced androgens via medical or surgical castration. The selective inhibitor of androgen biosynthesis Abiraterone (Abi), and the androgen receptor (AR) antagonist Enzalutamide (MDV3100), are second line hormonal therapies used to treat PC patients failing ADT. However, these drugs provide treatment response for a limited duration of time due to the development of resistance to them. Included among the mechanisms leading to resistance to ABI or MDV is the expression of the AR variant AR-V7. Metformin, a widely used oral anti-diabetic drug, has been reported to reduce prostate cancer mortality in PC patients with type II diabetes. In this study, we explored the effects of ABI, MDV and metformin in a pre-clinical model of PC. Both Abi and MDV inhibited cell proliferation and the expression of prostate specific antigen (PSA) in androgen-sensitive LNCaP cells. However, neither induced cell death, and in fact MDV appeared to actually inhibit apoptosis in LNCaP cells. Both agents increased AR and AR-V7 expression, which in part may account for development of resistance to ABI or MDV. In contrast, metformin inhibited AR, AR-V7 and PSA expression in a dose-dependent manner, and induced apoptotic cell death in PC cells. Metformin, in combination with ABI or MDV, further enhanced apoptosis and inhibited expression of PSA than it did as single agent. Interestingly, at near physiological concentrations metformin induced apoptosis in a caspase-independent manner rather than by a caspase-dependent apoptotic program that is reported to occur with high doses of metformin. In conclusion, Abi or MDV inhibits AR signaling and PC cell proliferation, but also induces AR and AR-V7 expression. Metformin decreases AR and AR-V7 expression and induces apoptotic cell death. The combination of metformin with androgen biosynthesis/AR inhibitors results in caspase-independent apoptotic cell death in addition to inhibition of both cell proliferation and AR signaling. Further studies will be needed to evaluate the clinical efficacy of these combination treatments in patients with PC. Citation Format: Yi Xie, Linbo Wang, Arif Hussain. Metformin enhances the anti-prostate cancer activity of abiraterone and enzalutamide. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 272.