Combination of Anti Diabetic and Anti‐Obesity Drugs Prevents Tumor Progression

Abstract

Obesity causes subclinical inflammation in adipose tissue that contributes to insulin resistance and cancer progression. Chronic inflammation predisposes to different forms of cancer, and diabetes is correlated with increased risk of breast cancer. Caloric restriction (CR) reduces insulin resistance, adiposity and inflammation and the anti‐diabetic drug metformin (MET) is a CR mimetic agent. In this study, we evaluated whether the combination of MET with the anti‐obesity drug orlistat (OR) enhances the anti‐cancer properties of MET on 4T1 cells, a highly metastatic breast cancer model. Combination of MET (5mM) + OR (10μM) significantly decreased in vitro cell proliferation (p<0.01), adhesion (p<0.05) and migration (p<0.01) compared to vehicle and each drug alone. 8‐weeks old female BALB/c mice received vehicle, MET (in drinking water, 3mg/ml), OR (240mg/kg/d) or MET + OR. After 3 weeks on drugs, 4T1 cells (105) were injected into mice and drugs continued till the end of the experiment. At 30 days, the MET + OR treatment induced a 50% reduction in tumor volume (p<0.01) and a significantly lower average wet tumor weight (p<0.01). Also, MET + OR treated mice had lower total vessel length (p<0.01) and a reduced number and size of spontaneous lung metastases (p<0.01). Our results provide a new rationale and experimental basis for the use of metformin plus orlistat as cancer therapy.