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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

Authors

  • Ali Muafaq Said

    Al-Amarah University College, Misan, Iraq

  • Ayat Ali Salih

    Department of Biology, College of Education for Pure Sciences, Tikrit University, Iraq

  • Mohammed Abdulridha Obid

    Al-Amarah University College, Misan, Iraq

  • Azal Hamoody Jumaa

    Bilad Alrafidain University, Iraq

  • Youssef Shakuri Yasin

    Iraqi National Cancer Research Center/the University of Baghdad, Iraq

DOI:

https://doi.org/10.30683/1929-2279.2025.14.26

Keywords:

Empagliflozin, Metformin, Cervical cancer, Metabolic disruption, Synergistic, cytotoxicity, Drug repurposing

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 and CPT1A, with docking scores of -7.4 and -8.7 kcal/mol for Empagliflozin and -5.2 and -5.1 kcal/mol for metformin, respectively. Suggesting dual inhibitory effects on CoA biosynthesis and fatty acid oxidation.

Conclusion: This study identifies the combination of Empagliflozin and Metformin as a promising candidate for repurposing as a therapeutic agent in cervical cancer. The therapeutic potential is supported by the well-characterized pharmacokinetics and established safety profiles of both agents, which are extensively used in the management of diabetes. The observed synergistic effect facilitates effective cytotoxicity at lower concentrations, thereby potentially minimizing adverse effects and enhancing the translational prospects of this metabolic-targeting strategy in clinical oncology trials.

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Published

2025-12-31

Issue

Vol. 14 (2025)

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Articles

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How to Cite

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. (2025). Journal of Cancer Research Updates, 14, 247-265. https://doi.org/10.30683/1929-2279.2025.14.26

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