A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways

Abstract

Metformin and phenformin, biguanide derivatives that are widely used to treat type 2 diabetes mellitus, have recently been shown to exert potential anticancer effects in prostate cancer. This study compared the anti-prostate cancer effects of the novel biguanide derivative IM176 with those of metformin and phenformin. Prostate cancer cell lines and patient-derived castration-resistant prostate cancer (CRPC) cells were treated with IMI76, metformin, and phenformin. The effects of these agents on cell viability, annexin V-FITC apoptosis, mTOR inhibition, protein expression and phosphorylation, and gene expression were evaluated. IM176 dose-dependently reduced the viability of all prostate cancer cell lines tested, with IC 50 s (LNCaP: 18.5 μM; 22Rv1: 36.8 μM) lower than those of metformin and phenformin. IM176 activated AMP-activated protein kinase (AMPK), inhibiting mTOR and reducing the phosphorylation of p70S6K1 and S6. IM176 inhibited the expression of androgen receptor (AR), the AR splice variant 7 (AR-V7) and prostate-specific antigen in LNCaP and 22Rv1 cells. IM176 increased caspase-3 cleavage and annexin V-positive/PI-positive cells, which indicated apoptosis. Moreover, IM176 reduced viability, with low IC 50 , in cultured cells derived from two patients with CRPC. The antitumor effects of IM176 were comparable with those of other biguanides. IM176 may therefore be a novel candidate for the treatment of patients with prostate cancer, including those with CRPC.