Abstract 4465: Miconazole induces cell cycle arrest and apoptosis in prostate cancer cells via a p53-mediated pathway: A Drug repurposing strategy.

Abstract Purpose of the study: This study explores the repurposing of FDA-approved antifungal drugs as potential therapeutics for prostate cancer. Background: Prostate cancer remains the second leading cause of cancer-related deaths among men in the United States. The American Cancer Society estimated about 313,780 new cases and 35,770 deaths projected from prostate cancer in 2025. Current treatments, including radiation, chemotherapy, hormone therapy, and other emerging modalities, are often associated with long-term adverse effects, underscoring the need for novel therapeutic strategies. Procedures: We screened antifungal drugs using CCK-8, colony formation, invasion, and migration assays to identify the most effective compound against prostate cancer cells. The lead hit molecule, miconazole, was further evaluated for its pro-apoptotic and cell cycle regulatory effects using confocal and scanning electron microscopy, flow cytometry, and Western blotting. Proteomic profiling and pathway enrichment analyses were performed to identify key molecular targets. The binding affinities of miconazole were evaluated via molecular docking. Results: Miconazole significantly inhibited prostate cancer cell proliferation, clonogenic capacity, invasion, and migration properties compared to other antifungal agents. Mechanistic studies revealed G0/G1 cell cycle arrest through downregulation of cyclin D3, CDK2, CDK4, and PCNA, and induction of apoptosis via upregulation of p53, p21, p27, cl-PARP, cl-caspase-3, alongside suppression of PARP-1 and caspase-3. Further, proteomic analysis revealed that miconazole significantly regulated many proteins that are responsible for cell cycle arrest and apoptosis. Molecular docking demonstrated that miconazole exhibited strong binding affinities with PARP1 (-8.97 kcal/mol) and cyclin D3 (-8.50 kcal/mol), moderate binding affinities with CDK4 (-7.19 kcal/mol) and CDK2 (-6.15 kcal/mol), and lower binding affinities with PCNA (-5.14 kcal/mol), TP53 (-4.89 kcal/mol), and CDKN1B (-3.50 kcal/mol). No significant binding was found with caspase-3 (+65.04 kcal/mol). Conclusions: These findings highlight miconazole as a promising candidate for drug repurposing in prostate cancer therapy, offering a potential foundation for future combination strategies. Citation Format: Eswara Naga Hanuma Kumar Ghali, Lindsey Shim, Rahul Tiwari, Rajasekhar Baru, Anupam Dhasmana, Chang Ryan Jisoo, Sung Yun Jung, Vivek Kumar Kashyap, Neeraj Chauhan, Subhash C. Chauhan, Murali M. Yallapu. Miconazole induces cell cycle arrest and apoptosis in prostate cancer cells via a p53-mediated pathway: A Drug repurposing strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4465.