Metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer

Abstract

The present study aimed to evaluate the effect of metformin pretreatment on the potentiation of antiproliferative action of doxorubicin against breast cancer. Female Wistar rats were administered with 7,12-Dimethylbenz(a)anthracene (DMBA) (35 mg) in 1 ml olive oil subcutaneously beneath the mammary gland. Animals were pretreated with metformin (Met) 200 mg/kg two weeks before DMBA administration. DMBA control groups received doxorubicin (Dox) (4 mg/kg and 2 mg/kg), Met (200 mg/kg) alone and in combination with Dox (4 mg/kg). Met pre-treated DMBA control groups received Dox 4 mg/kg and 2 mg/kg. Met pre-treated groups treated with Dox exhibited a decrease in tumor incidence, tumor volume and increased survival rate than the DMBA group. Organ-to-body weight ratios and histopathology of heart, liver and lungs of Met pre-treated groups treated with Dox showed lesser toxicity than Dox treated DMBA control groups. There was a noteworthy decrease in malondialdehyde levels and a substantial increase in the levels of reduced glutathione together with a significant decrease in the levels of inflammatory markers like IL-6, IL-1β and NF-κB in Met pre-treated groups treated with Dox. Histopathology of breast tumors revealed better control of tumors in Met pre-treated groups treated with Dox than DMBA control group. Immunohistochemistry and real-time PCR data revealed a significant reduction in Ki67 expression in Met pre-treated groups treated with Dox as compared to the DMBA control group. The present study suggests that metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer.