A Repurposed Duo: Empagliflozin-Metformin Triggers a Metabolic Crisis in Cervical Cancer by Disrupting the Acyl-CoA/CoA Ratio via Dual Inhibition of PPAT and CPT1A
Abstract
Objective: This study aimed to assess the cytotoxic, selective, and synergistic effects of an Empagliflozin-Metformin mixture against HeLa cervical cancer cells and to investigate its underlying mechanism of action, especially through metabolic disruption.
Materials and Methods: The cytotoxic effects of Empagliflozin, Metformin, carboplatin, and their mixture were evaluated in HeLa and human foreskin fibroblast (HFF) cells using the MTT assay at 24 and 72 hours. The Combination Index (CI) and Dose Reduction Index (DRI) were calculated to assess drug interactions. Metabolic disruption was analyzed by measuring the intracellular Acyl-CoA/CoA ratio. Molecular docking simulations were performed to predict binding affinities for key metabolic enzymes, Phosphopantetheine Adenylyl Transferase (PPAT) and Carnitine Palmitoyl Transferase 1A (CPT1A).
Results: The mixture showed clear, time-dependent cytotoxic effects on HeLa cells, with an IC₅₀ of 207.5 µg/ml at 72 hours, which is significantly lower than the IC₅₀ values of either agent alone. The combination exhibited high selectivity toward malignant cells, with a Selectivity Index of over 4.82, and demonstrated strong synergistic interactions, as indicated by a combination index (CI) of less than 1.0. Additionally, a dose-dependent increase in the Acyl-CoA/CoA ratio was observed (5.02 ± 0.41 at 1000 µg/ml), indicating considerable metabolic stress. Molecular docking analyses showed strong binding affinities for both drugs to PPAT…
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