Investigation of Effect of Metformin and Hesperidin in Combination with Doxorubicin in Experimentally Induced Breast Cancer

Abstract

Breast cancer is the leading cause of cancer worldwide affecting women. There is an increase newlinein the breast cancer incidence and mortality among women. For high-risk women patients, newlinetamoxifen and raloxifene are being used as a chemopreventive approach. Metformin, widely newlineused as anti-diabetic, has gained momentum for its preventive potential and delaying various newlinecancers including breast cancer owing to its high safety profile and better tolerability. newlineHesperidin, a bioflavonoid, is commonly found in citrus fruits like lemon and orange, which newlineis an integral part of daily diet and consumed worldwide. Hesperidin possess potent newlineantioxidant, anti-inflammatory, anticancer and chemopreventive activity in various cancers. newlineEven though, doxorubicin (Dox) is routinely used for breast cancer treatment but toxicity and newlinedrug resistance limit its use. Hence, the aim of the current study was to evaluate the newlineprotective effect of metformin and hesperidin alone and in combination with doxorubicin in newlineexperimentally-induced breast cancer. In vitro assays such as cell viability assay, scratch newlineassay, annexin V FITC assay and cell cycle analysis were carried out using MDA-MB-468 newlineand MDA-MB-231 human breast cancer cell lines. IC50 concentration of doxorubicin newlineshowed potentiation of antiproliferative effect of doxorubicin when combined with lower newlineconcentration of metformin or hesperidin or both. The assays revealed that metformin and newlinehesperidin in combination with doxorubicin showed decrease in migration rate of cells, newlineincrease in the cells undergoing apoptosis and shift of cells from G0/G1 phase of cells to S newlinephase of cell cycle, ultimately leading to cell cycle arrest in S phase. Whereas, in in vivo newlinestudy, breast cancer (BC) was induced by administration of 7,12-dimethylbenz(a)anthracene newline(DMBA) through subcutaneous injection into the 3rd right mammary gland of newlinefemale Wistar rats. The experimental groups comprised treatment groups and preventive newlinegroups with metformin and hesperidin receiving as pretreatment 2 weeks prior to DMBA