Abstract 5564: Lack of efficacy of metformin in several standard prevention models: Methylnitrosourea rat mammary (ER+), MMTV-Neu/p53 mouse mammary (ER−) and the Min mouse colon

Abstract

Abstract Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated considerable interest as a potential preventive agent for a variety of cancers. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. The preventive efficacy of metformin was examined in three commonly employed in rodent prevention models of breast and intestinal cancers. Treatment of female Sprague-Dawley rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers. This model has been highly responsive to a wide variety of agents or hormonal alterations that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, and ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day; beginning seven days after MNU treatment and continuing for the duration of the study. Metformin failed to decrease mammary cancer incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53 KO mice (which spontaneously develop ER− cancers) was evaluated. In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and continued for 10 months. This study similarly showed no efficacy of metformin (average tumors/mouse: 2.7 in both controls and metformin-treated mice). Finally the effect of metformin was examined in the Min model of intestinal neoplasia, in which mice have a germline APC mutation. Again, we failed to observe any efficacy of metformin. In contrast, naproxen (a non-specific NSAID) was highly effective in this model when used as a positive control. Thus, these initial studies failed to detect any chemopreventive efficacy of metformin in three commonly employed prevention models. One major caveat to these studies is that the animals were not diabetic nor were they administered an altered diet containing high fat or carbohydrates. Supported by NCI contract number HHSN261200433001C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2011-5564