Obesity has been associated with a worse prostate cancer prognosis and increased levels of insulin are thought to mediate this effect. It has been established that hyperinsulinemia associates with higher levels of insulin receptors (IR) in prostate cancers and increased tumor growth. Men with prostate cancer who are put on androgen blockade (ADT) develop increased insulin resistance, with mild hyperinsulinemia. It is possible that this can contribute to the development of castrate resistant prostate cancer (CRPC).

Metformin through interactions of AMPK in the liver, inhibits gluconeogenesis and reduces circulating insulin levels, potentially reducing insulin-stimulated cancer growth. It is also possible that intracellular AMPK activation, as it has been shown in vitro breast, ovarian and PC cell lines have a direct antitumor effect.

C. Ferrario etal. analyzed a tissue-microarray of 644 prostate samples, including benign lesions and low to high Gleason scores. In vitro, PC-3 cells were exposed to increasing concentrations of metformin (up to 20.0 mM), with or without 24-hour preincubation with siRNA against AMPK or control siRNA. Protein sythesis was assessed by

[35S]methionine metabolic labeling.

In vitro, metformin caused a dose-dependent growth inhibition of PC-3 cells, together with an increase in activated phospho-AMPK. The effect of inhibiting concentrations of metformin was also evident as a reduction in general protein synthesis. Importantly, siRNA-mediated decrease in AMPK substantially rescued cells from the growth inhibitory effect of metformin.

Metformin inhibits growth of PC cells, mainly by increasing AMPK function. It is therefore a viable candidate agent for the treatment of PC. The researchers are planning a placebo-controlled study in androgen blockade-resistant disease to verify this effect.

C. Ferrario, M. Zakikhani, M. E. Cox, M. E. Gleave, M. N. Pollak; McGill University, Montreal, QC, Canada; University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada

ASCO 2010 Genitourinary Cancers Symposium
General Poster Session A: Prostate Cancer
Abstract No: 83

Joel T Nowak, MA, MSW