The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

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 G 0 /G 1 . 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.

Does diabetes therapy influence the risk of cancer?

“…Rapamycin, the inhibitor of mTOR, and its derivatives have been tested in several cancer trials with some success. A study of human prostate cancer cells demonstrated a strong anti-proliferative effect of metformin [13]. This effect was unaffected by inhibition of the AMPK pathway, but was associated with cell cycle arrest in G 0 /G 1 phase, together with a major reduction in cyclin D1 levels.…”

Antiproliferative action of metformin in human lung cancer cell lines

“…Mazzone et al reported that diabetes patients with lung cancer who were previously treated with metformin or thiazolidinediones had a lower incidence of metastatic disease at the time of diagnosis and a reduced risk of death compared to those who did not receive the same treatment (4). Thereafter, the antiproliferative action of metformin was confirmed via in vivo and in vitro experiments in various cancer cell lines including breast (5)(6)(7)(8), prostate (9), pancreas (10), and ovarian cancer (11)(12)(13) as well as lung adenocarcinoma (8).…”

“…Despite these findings, the precise mechanisms of the metformin-induced effects are not fully understood. In particular, controversy remains about whether metformin is apoptotic (6,10) or just cytostatic (5,9) and whether it kills cancer cells synergistically with cytotoxic agents including cisplatin (11,13), paclitaxel (8), and doxorubicin (17), or if it is antagonistic to cisplatin (18,19).…”

Les nouvelles promesses de la metformine

“…En accord avec ces résultats, le traitement de cellules cancéreuses du poumon et du sein par la metformine provoque un blocage du cycle cellulaire en phase G2/M et une augmentation de l'apoptose. Dans les lignées cellulaires de cancer de la prostate, la metformine induit un arrêt du cycle cellulaire en phase G0/G1 par l'intermédiaire d'une diminution de l'expression de la cycline D1 [33] (Figure 3). …”

“…Ce résultat a été conforté par de nombreuses évidences obtenues in vitro montrant que la metformine inhibe directement la prolifération des cellules cancéreuses [32,33]. Il est important de noter que la sensibilité des cellules tumorales à la metformine est variable, et l'effet antiprolifératif n'est observé que pour de fortes concentrations de metformine (5-50 mM), bien supérieures à celles obtenues pour un usage thérapeutique chez le diabétique (concentrations plasmatiques de l'ordre de 10 à 40 μM).…”