Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models

Abstract

Objective: There is increasing preclinical evidence indicating that metformin, a medication commonly used for type 2 diabetes mellitus, may protect against cancer. Motivated by this emerging evidence we asked 2 questions: (1) can metformin prevent ovarian cancer growth by altering metabolism and (2) will metformin increase sensitivity to chemotherapy.

Study design: The effect of metformin in ovarian cancer was tested in vitro and with 2 different mouse models. In vitro, cell lines (n = 6) were treated with metformin (10-40 mmol/L) or phosphate-buffered saline solution and cellular proliferation and metabolic alterations (adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis) were compared between the 2 groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/d intraperitoneally) or placebo for 2 weeks followed by intraperitoneal injection of the SKOV3ip1 human ovarian cancer cell line, and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-ras(G12D/+)/PTEN(floxP/floxP) genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/wk intraperitoneally for 7 weeks), metformin (100 mg/kg/d in water for 7 weeks), or paclitaxel plus metformin, and tumor volume was compared among treatment groups.

Results: In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice that were pretreated with metformin had 60% fewer tumor implants compared with controls (P < .005). In the treatment study, mice that were treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared with controls (P = .02), which is a level of tumor reduction greater than that resulting from either paclitaxel or metformin alone.

Conclusion: Based on these results, we conclude that metformin alters metabolism in ovarian cancer cells, prevents tumor growth, and increases sensitivity to chemotherapy in vitro and in mouse models. These preclinical findings suggest that metformin warrants further investigation for use as an ovarian cancer therapeutic.

Keywords: cancer; metabolism; metformin; mouse model; ovarian cancer; prevention.