Ellagic Acid and Metformin: In Vitro Synergy and Enhanced Cisplatin Efficacy In Vivo in Resistant Breast Cancer

Cisplatin resistance remains a significant challenge in the effective treatment of breast cancer, underscoring the need for novel combination-based therapeutic strategies. Background: This study investigated the anticancer effects of ellagic acid (EA) and metformin (MET), both individually and in combination, against parental and cisplatin-resistant breast cancer models. To our knowledge, this is the first study to evaluate the EA-MET combination in the context of cisplatin resistance in breast cancer. Methods: The in vitro antiproliferative and apoptotic effects of EA and MET were assessed using MTT and caspase-3 assays in parental (EMT-6/P) and cisplatin-resistant (EMT-6/CPR) cells. An in vivo study was also conducted to evaluate the anti-tumor effects of the treatment combinations in mice bearing EMT-6/P or EMT-6/CPR tumors. Liver enzymes and creatinine levels were measured to assess potential hepatic and renal toxicity. Results: In vitro combination index analysis indicated a synergistic interaction between EA and MET in EMT-6/P cells (CI = 0.45) and a strong synergistic interaction in EMT-6/CPR cells (CI = 0.29) under the tested conditions. In vivo, the addition of the combination to cisplatin resulted in significant tumor size reductions of 73.83% and 56.25% in EMT-6/P and EMT-6/CPR bearing mice, respectively, along with tumor regressions of 66.6% and 50%, respectively. Conclusions: Thecombination of metformin and ellagic acid shows promise as a potential treatment for cisplatin-resistant breast cancer. Further research is needed to elucidate the precise anticancer mechanisms underlying this combination.