99 UTILIZING METFORMIN TO ENHANCE THE EFFICACY OF ANDROGEN DEPRIVATION THERAPY IN THE TREATMENT OF PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Prostate cancer (PCa) incidence varies dramatically by geographic location, with developed countries exhibiting significantly higher levels of disease. Some attribute this to the ‘Westernized lifestyle’ of high energy diets and limited physical activity with consequent obesity. Obesity and obesity-related diseases like diabetes, cause hyperinsulinemia, which upregulates pro-survival insulin/insulin-like growth factor signalling. Our previous work shows diet-induced hyperinsulinemia to enhance PCa tumor growth in vivo. Metformin, a treatment for diabetes, reduces hyperinsulinemia, and has recently been shown to exhibit anti-neoplastic properties. We assessed the potential additive benefit of combining a standard PCa treatment (androgen ablation therapy with bicalutamide) with metformin in vitro and in vivo. METHODS: Using clonogenic assays we assessed the effect of bicalutamide and/or metformin on colony formation rates in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines. Western blot and cell cycle analyses were used to elucidate any mechanism of interaction between the two drugs in androgen receptor (AR) positive (LNCaP) and AR negative (PC3) cell lines. The combination treatment regimen was then assessed in vivo using a LNCaP murine xenograft model. RESULTS: Micromolar bicalutamide or millimolar metformin caused significant dose-dependent reduction in colony formation rates (p 0.001). Combination treatment further significantly reduced colony formation rates (p 0.005). The effect was more pronounced in AR positive cells. Western blot and cell cycle analyses suggested differing mechanisms of interaction in AR positive and negative cell lines. Following combination treatment LNCaP cells exhibited altered cell proliferation (decreased PCNA) and perturbed cell cycle kinetics (G1/S arrest). Conversely, PC3 cells showed evidence of enhanced apoptosis (increased BAX, decreased caspase 3 and phospho-Akt). Preliminary in vivo results show significantly diminished tumor growth in response to the combination treatment regimen (p 0.0001). CONCLUSIONS: Combining bicalutamide and metformin significantly reduces PCa cell colony formation rates further than either monotherapy. In AR positive cells this effect is mediated by reducing cellular proliferation rates, whereas in AR negative cells the combination treatment regimen promotes apoptosis. This combination drug regimen may potentially improve prostate-cancer specific survival via the direct anti-neoplastic properties outlined.