Combination of Simvastatin and Metformin Reduces Triple‐Negative Breast Cancer Tumor Growth Through AKT/AMPK/ACC Signaling Axis

Chemotherapy continues to be the standard of care for metastatic malignancies, such as triple-negative breast cancer (TNBC). Although the treatment strategy increases survival rates marginally, it frequently leads to the development of resistant disease and side effects. It is imperative to develop an alternate chemotherapy formulation with better efficacy and lesser adverse effects in TNBC patients. Cell viability and cholesterol level were measured using spectrophotometer and fluorometric assays. The 4T1 syngeneic BALB/c female mice were used as an in vivo metastatic TNBC model. Simvastatin (Sim) and Metformin (Met) were administered in combination (3.5-7.0 and 175-350 μg/g body weight, respectively) and alone (Sim 7.0 μg/g/day, or Met 350 μg/g/day) orally over an 8-week period, and the standard Anticancer drug docetaxel (Doc) was administered at a dose of 24 μg/g body weight through IP injection every 3 weeks. Phosphorylation levels of protein and histopathology of tumors were studied by immunoblot and H & E staining methods, respectively. We report that the viability of TNBC cells is significantly and synergistically reduced by Sim and Met co-treatment, with negligible adverse effects on normal breast cell line. Sim Met combination down regulates phosphorylation at specific sites of AKT (Ser-473/Thr-308) and AMPKα (Ser-485/491) and up regulates ACC phosphorylation (Ser-79), which in turn minimizes the cellular cholesterol synthesis in the TNBC model. Further study demonstrated that the combination significantly reduced tumor formation effectively than docetaxel. Study confirmed that the combination of Sim and Met is a promising chemotherapeutic approach for metastatic TNBC.