Abstract 1250: Evaluation of the prevention by pioglitazone/metformin of ER-positive and ER-negative mammary cancers occurring in rodents on a high-fat diet

Abstract

Abstract Both metformin and pioglitazone have demonstrated cancer chemopreventive properties. Actoplus/Met, a combination of the two agents, is currently used in the clinic with an additive effect on improving insulin resistance, a proposed risk factor for certain cancers. Based on this prior knowledge, we tested pioglitazone and metformin individually and in combination for preventive efficacy in both rat (ER-positive) and mouse (ER-negative) mammary cancer models, using high-fat and high-fructose diets. Pioglitazone in both rats and mice at doses as high as 20 mg/kg BW/day, 7X/week was not toxic, although the high-fat diets resulted in weight gain. Rats: Pioglitazone alone in rats receiving a high-fat diet led to a 2% increase in mammary cancer multiplicity at a high dose (20 mg/kg BW/day) and a 21% decrease in multiplicity at a low dose (10 mg/kg BW/day). In rats fed a high-fructose diet, the combination of pioglitazone and metformin caused a 20% decrease in multiplicity, in contrast to pioglitazone alone which led to a 10% decrease in mammary cancer number. In rats fed a high-fat diet, the combination caused a 24% increase versus a 1.0% decrease in cancer multiplicity with pioglitazone alone. Mice: Pioglitazone alone at a high or low dose (20 or 10 mg/kg BW/day) in mice fed a high-fat diet resulted in a 28% and 47% reduction in mammary cancer multiplicity, respectively. In mice fed a high-fructose diet in a combination study, pioglitazone alone caused a 7% decrease in mammary cancer whereas the combination of pioglitazone with metformin showed no effect on mammary cancer reduction. Metformin alone in rats on a high-fat diet caused a 35% decrease in mammary cancer multiplicity at 150 mg/kg BW/day but a 9% decrease at 300 mg/kg BW/day. Metformin alone in rats on a high-fructose diet caused an 11% increase but the combination with pioglitazone caused a 20% decrease in cancer multiplicity. When rats were given a high-fat diet, metformin alone caused a 14% decrease and in combination with pioglitazone caused a 24% decrease in ER-positive mammary cancers. The conclusions are: (1) Pioglitazone is not active as a chemopreventive agent when given alone or in combination with metformin in rats treated with MNU on a high-fat or a high-fructose diet. (2) Pioglitazone is not active as a chemopreventive agent when given alone or in combination with metformin in MMTV/Neu mice treated with DMBA on a high-fat or a high-fructose diet. (3) Metformin is not active as a chemopreventive agent when given alone or in combination with pioglitazone in rats treated with MNU on a high-fat or a high-fructose diet. (4) Metformin showed some chemopreventive efficacy when given alone to MMTV/Neu mice receiving DMBA and on a high-fat diet. Efficacy was also observed with metformin alone and in combination with pioglitazone in mice receiving a high-fructose diet. Citation Format: Barbara K. Dunn, Chen Suen, Clinton Grubbs. Evaluation of the prevention by pioglitazone/metformin of ER-positive and ER-negative mammary cancers occurring in rodents on a high-fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1250.