Pharmacological combination of simvastatin and doxorubicin reduces tumor growth and lung metastasis in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking expression of estrogen, progesterone, and HER2 receptors, limiting the efficacy of targeted therapies. Patients with TNBC face a poor prognosis, with a median survival of less than 5 years. Drug repurposing has emerged as a promising strategy to improve therapeutic options and overcome resistance in TNBC. METHODS: We evaluated the antitumor efficacy of simvastatin, a cholesterol-lowering drug, in combination with doxorubicin using MDA-MB-231 TNBC cells and spheroids, and an orthotopic mouse TNBC model. The cells and spheroids were treated with doxorubicin either individually or in combination with simvastatin to assess the effects on viability, migration, and invasion. In vivo, tumor-bearing mice were administered doxorubicin (1 mg/kg, i.v.) and/or simvastatin (20 mg/kg, oral) twice weekly for 3 weeks. Primary tumor growth was monitored using a caliper and near-infrared fluorescence imaging (NIRF), while their metabolic activity was assessed by micro-PET/CT with 18F-fluorodeoxyglucose (18F-FDG). The pulmonary metastasis was assessed via NIRF imaging and histological analysis. RESULTS: In vitro, the combination of simvastatin and doxorubicin significantly inhibited MDA-MB-231 cell proliferation, migration, and invasion, compared to either treatment alone; and in spheroids, the cytotoxicity was significantly decreased. In vivo, the doxorubicin/simvastatin combination significantly decreased the tumor growth rate and the pulmonary metastasis. Histopathological analysis of lung sections showed reduced neoplastic infiltration, and Ki-67 immunohistochemistry showed decreased cellular proliferation in the combination group. CONCLUSION: Our findings suggest that simvastatin enhances the therapeutic response of doxorubicin and may represent a valuable adjuvant strategy to control metastatic progression in TNBC.