Miconazole as a Repurposed Anticancer Candidate for Prostate Cancer.

Prostate cancer is one of the major health concerns, with increasing incidence and persistent therapeutic resistance worldwide. Despite various available treatments (radiation therapy, chemotherapy, hormone therapy, cryotherapy, biological therapy, and high-intensity focused ultrasound), patients still show treatment-related side effects over many years. These challenges highlight the urgent need for novel and safe therapeutic strategies. In the present study, we repurposed five FDA-approved antifungal agents, namely natamycin (NM), terbinafine hydrochloride (TH), ketoconazole (KZ), miconazole (MZ), and clotrimazole (CZ), as they can modulate conserved cellular processes, including sterol metabolism and mitochondrial function, which are increasingly recognized as critical determinants of cancer cell survival. Our data demonstrated MZ as the most active compound that significantly reduced prostate cancer cell viability, clonogenic growth, invasion, and migration compared with other tested antifungal agents. Later, proteomic profiling revealed that MZ alters key regulators of cell-cycle progression and apoptotic signaling pathways. Furthermore, pathway enrichment analysis revealed prostate cancer as one of the top enriched pathways, p53 signaling, and other associated pathways. These findings were validated by microscopy, flow cytometry, and protein expression analyses, demonstrating that MZ induces morphological changes and G0/G1 cell-cycle arrest via downregulation of cyclin D3, CDK2, CDK4, and PCNA and activates p53-associated signaling changes characterized by increased p21 and p27 expression. These findings identify MZ as a mechanistically active repurposed candidate for prostate cancer and support further exploration for oncology drug repurposing strategies.