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

Abstract

OBJECTIVE There is increasing pre-clinical evidence indicating that metformin, a medication commonly used for type 2 diabetes, may protect against cancer. Motivated by this emerging evidence we asked two questions: (a) can metformin prevent ovarian cancer growth by altering metabolism, and (b) will metformin increase sensitivity to chemotherapy. STUDY DESIGN The effect of metformin in ovarian cancer was tested in vitro and by using two different mouse models. In vitro, cell lines (n=6) were treated with metformin (10 to 40 mM) or PBS and cellular proliferation and metabolic alterations (AMP-activated protein kinase activity, glycolysis, lipid synthesis) were compared between the two groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/day intraperitoneal (i.p.)) or placebo for 2 weeks followed by i.p. 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-rasG12D/+/PTENfloxP/floxP genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/week i.p. x 7 weeks), metformin (100 mg/kg/day in water x 7 weeks), or paclitaxel plus metformin and tumor volume was compared between 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 AMP-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice pre-treated with metformin had 60 % fewer tumor implants compared to controls (p<0.005). In the treatment study, mice treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared to controls (p=0.02); 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 pre-clinical findings suggest that metformin warrants further investigation for use as an ovarian cancer therapeutic.

Aspirin and metformin exhibit antitumor activity in murine breast cancer

“…Metformin therapy weakens the risk of glioma-initiating cells (48), and inhibits ovarian cancer by increasing sensitivity to cisplatin (49,50), endometrial cancer through changes in Ki-67 proliferation (51-53), and breast cancer (54,55) and non-small cell lung carcinomas (56,57). Laboratory studies on breast cancer have shown that metformin increases the mean life span by 8% and mammary adenocarcinoma latency by 13.2% (P<0.05) in HER2/neu mice (58).…”

Evaluation of Effects of Metformin in Primary Ovarian Cancer Cells

“…Metformin intake is associated with better survival in ovarian cancer (Kumar et al, 2013), reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus (Tseng et al, 2015), targets ovarian cancer stem cells in vitro and in vivo (Shanka et al, 2012), limits the adipocyte tumor promoting effect on ovarian cancer (Tebbe et al, 2014), prevents aggressive ovarian cancer growth driven by high energy diet (Wahab et al, 2015). Moreover, metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models (Lengyel et al, 2015).…”

Increased efficacy of metformin corresponds to differential metabolic effects in ovarian tumors in obese versus lean mice

“…As seen in previous studies of metformin in OC mouse models [73][74][75], metformin inhibited tumor growth in the KpB mouse model. However, while metformin inhibited tumor growth in both the HFD-and LFD-fed mice, metformin had a more potent effect in the HFDfed mice (60% decrease in HFD-fed mice, 32% decrease in LFD-fed mice).…”