In addition, hyperinsulinemia may facilitate tumor growth. This paper shows that metformin, the oral diabetic medication and known autophagy inhibitor augments bicalutamide’s effects on prostate cancer cell growth. Obesity and obesity-related diseases like diabetes,cause hyperinsulinemia, which upregulates pro-survival insulin/insulin-like growth factor signaling. These investigators have previously shown that diet-induced hyperinsulinemia enhances prostate cancer tumor growth in vivo. Metformin reduces hyperinsulinemia, and has anti-neoplastic properties. This study combined metformin with the anti-androgen bicalutamide to assess the potential additive benefit in vitro and in vivo. Clonogenic assays were used to assess the effect of bicalutamide and/or metformin on colony formation rates in LNCaP, PC3, DU145 and PC3AR2 prostate cancer cell lines. Western blot and cell cycle analyses were used to elucidate any mechanism of interaction between the two drugs in androgen receptor positive LNCaP and AR negative PC3 cell lines. The combination treatment regimen was also assessed in vivo using an LNCaP murine xenograft model.
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 and perturbed cell cycle kinetics with G1/S arrest. Conversely, PC3 cells showed evidence of enhanced apoptosis with increased BAX, decreased caspase 3 and phospho-Akt. In vivo results show significantly diminished tumor growth in response to the combination treatment regimen (p<0.0001).
Presented by Alexandra Colquhoun, et al. at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.
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