Miconazole as a repurposed therapeutic candidate for prostate cancer.

Abstract

e17130 Background: Prostate cancer remains a leading cause of cancer-related morbidity and mortality worldwide, despite significant advances in diagnosis and therapy. Current treatment options are often associated with long-term adverse effects and the development of therapeutic resistance, underscoring the need for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to rapidly identify novel anticancer agents with established safety profiles. In this study, we explored the anticancer potential of selected FDA-approved antifungal drugs as repurposed therapeutics for prostate cancer. Methods: Five antifungal agents, natamycin, terbinafine, ketoconazole, miconazole, and clotrimazole, were evaluated for anticancer activity in prostate cancer (C4-2 and DU145) cell lines using CCK-8 cell viability, colony formation, and invasion and migration assays. Proteomic profiling was performed to identify differentially expressed proteins, followed by pathway enrichment analysis to elucidate affected signaling networks. The most effective compound was further investigated using confocal and scanning electron microscopy, flow cytometry, and Western blotting to assess cellular morphology, cell-cycle distribution, and apoptosis. Molecular docking studies were conducted to evaluate binding interactions between miconazole and key proteins involved in cell-cycle regulation and apoptosis. Results: Among the tested antifungal agents, miconazole exhibited the strongest anticancer activity, significantly reducing cell viability, clonogenic survival, and invasive and migratory capacities of prostate cancer cells. Proteomic analysis confirmed significant modulation of proteins associated with cell-cycle control and apoptosis, with pathway enrichment highlighting prostate cancer and p53 signaling pathways. Mechanistic studies revealed that miconazole induced marked morphological and nuclear alterations, caused G0/G1 cell-cycle arrest through downregulation of cyclin D3, CDK2, CDK4, and PCNA, and promoted apoptosis via activation of p53-associated pathways, including upregulation of p53, p21, p27, cleaved PARP, and cleaved caspase-3. Molecular docking demonstrated strong binding affinities of miconazole toward PARP1 and cyclin D3, supporting its mechanistic role in growth inhibition and apoptosis induction. Conclusions: This study demonstrates that miconazole possesses potent anticancer activity against prostate cancer cells and highlights its potential as a repurposed therapeutic agent.