Synergistic Antitumor Effects of Lovastatin and Arsenic Trioxide Combination on the MDA-MB-231 Breast Cancer Cell Line: A Drug Repositioning Approach

Abstract

Background: Triple-negative breast cancer (TNBC) lacks hormone- or HER2-targeted therapies and remains associated with early relapse and therapeutic resistance. Targeting metabolic pathways has emerged as a complementary approach to conventional cytotoxic therapy. The mevalonate pathway supports oncogenic signaling through prenylation-dependent activation of small GTPases, whereas arsenic trioxide (As2O3) induces oxidative stress-mediated apoptosis, thereby reducing cell viability. Objectives: This study investigated whether pharmacologic inhibition of HMG-CoA reductase with lovastatin (Lov) enhances the cytotoxic efficacy of As2O3 in TNBC cells. Methods: The human TNBC cell line MDA-MB-231 was treated with Lov and As2O3 as monotherapies and in combination. Cell viability was assessed using MTT assays and morphological evaluation. Long-term proliferative capacity was evaluated using clonogenic survival analysis. Drug interactions were quantified using the Chou-Talalay method, including combination index (CI) calculations and isobologram modeling. Results: Lov and As2O3 each reduced cell viability in a concentration-dependent manner, with IC50 values of approximately 2 µM and 7.5 µM, respectively. Combined treatment produced synergistic growth inhibition across multiple concentration ratios (CI < 1), enabling significant cytotoxicity at lower drug concentrations. Clonogenic assays showed marked suppression of colony formation after combination exposure compared with single-agent treatment, indicating an impaired long-term proliferative potential. Conclusions: Lov enhances the in vitro antitumor activity of As2O3 in MDA-MB-231 TNBC cells, supporting the potential for metabolic sensitization by targeting the mevalonate pathway. Although these findings are limited to a single cell line and require mechanistic and in vivo validation, they support further preclinical investigation of statin-based combination therapies in TNBC.