A Repurposed Drug Combination Overcomes Paclitaxel Resistance and Minimizes Toxicity via Dual Metabolic and pH Modulation in Breast Cancer

Abstract

Background: Paclitaxel (PTX) remains a cornerstone in breast cancer treatment, but its effectiveness is limited by both chemoresistance and significant side effects. A promising strategy to overcome these challenges is to repurpose existing drugs. The present investigation sought to explore the combined anticancer efficacy of a new triple-combination treatment. included paclitaxel, dapagliflozin, and pantoprazole, specifically targeting MCF-7 breast cancer cells. and evaluated the safety profile of this combination in normal human foreskin fibroblasts (HFF). Materials and Methods: Cytotoxicity was assessed using the MTT assay. The degree of synergy was assessed using the Combination Index (CI) and the Dose Reduction Index (DRI). Furthermore, the underlying molecular mechanisms were investigated using ELISA-based quantification of relevant biomarkers, including HIF-1α, p-mTOR, Cathepsin D, LC3B-II, Cleaved Caspase-3, NF-κB, HO-1, Bcl-2, and Bax. These findings were subsequently corroborated by in silico molecular docking studies targeting PDK1, SGLT2, Cathepsin D, MMP9, TRPV1, and COX-2. Results: The triple combination exhibited potent, synergistic cytotoxic effects on MCF-7 cells, as evidenced by a significantly lower IC50 value (4.1 μg/mL at 72 hours) and a high selective toxicity index (>243.9). Synergism was further substantiated by CI values. This combination treatment downregulated HIF-1α and p-mTOR, inhibited Cathepsin D, activated autophagy (LC3B-II), and induced apoptosis (cleaved caspase-3). Furthermore, in HFF cells, it alleviated paclitaxel-induced stress and inflammation. Docking analyses showed favorable binding affinities of dapagliflozin to PDK1, SGLT2, and TRPV1, with docking scores of -8.4, -8.3, and -8.4 kcal/mol, respectively. Pantoprazole showed favorable binding affinities to cathepsin D1, MMP9, and COX-2, with docking scores of -8.3, -9.0, and -8.8 kcal/mol, respectively. Conclusion: The triple mixture exhibits potent, targeted anticancer effects by disrupting pathways that support cancer cell survival while safeguarding normal cells. This strategy offers a promising avenue to overcome paclitaxel resistance and minimize associated side effects.