1. ¹INSERM U568, Nice, France
2. ²Université de Nice Sophia Antipolis, IFR50, Nice, France
3. ³INSERM U638, Nice, France
4. ⁴INSERM U526, Nice, France

Correspondence: Dr F Bost, Université de Nice Sophia-Antipolis, INSERM U568, Bâtiment ARCHIMED, 151 Route de St Antoine de Ginestière, BP 2 3194, NICE Cedex 03 06204, France. E-mail: bost@unice.fr

Received 20 September 2007; Accepted 3 December 2007; Published online 21 January 2008.

Abstract

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G₀/G₁. This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27^kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.