Repurposing α-Blockers Alfuzosin and Doxazosin for Cancer Therapy: Integrated Experimental, Mechanistic, and Molecular Docking Studies

Background/Objectives: Drug repurposing represents a promising strategy for determining new anticancer drugs through exploration of new therapeutic applications of clinically used drugs. Alfuzosin and doxazosin are α-adrenergic blockers clinically used for the treatment of benign prostatic hyperplasia (BPH). Growing evidence suggests that α-blockers may have anticancer properties. The purpose of this study was to investigate the potential of alfuzosin and doxazosin as repurposed anticancer medicines and to study their potential mechanisms of action, specifically their effects on apoptosis, cell cycle progression, enzyme panel, and cancer cell proliferation. Methods: The cytotoxicity of alfuzosin and doxazosin was investigated against multiple cancer cell lines using the MTT assay, with sunitinib used as a positive control. The enzyme inhibition effects of both drugs against potential target proteins were investigated, followed by cytometric analysis to determine the effects of the drugs on cell cycle progression and apoptosis in MCF-7 breast cancer cells. Molecular docking studies were also conducted to investigate possible interactions with the active site of EGFR. Results: Both alfuzosin and doxazosin demonstrated promising antiproliferative activity against cancer cells, with alfuzosin showing comparatively lower toxicity toward normal cells. The drugs also revealed potent inhibitory activity against the studied target proteins, pointing to their potential effect as multi-target inhibitors. Cell cycle analysis revealed that both drugs inhibited cell cycle progression at the G2/M phase in MCF-7 cells. Following treatment with alfuzosin and doxazosin, both drugs significantly induced apoptosis, with total apoptotic populations reaching 39.48% and 35.61%, respectively, compared with only 2.77% in untreated MCF-7 cells. Molecular docking studies further indicated the ability to interact with key amino acids within the EGFR active site. Conclusions: The present findings demonstrate the potential repurposing of alfuzosin and doxazosin as anticancer agents and offer a good background for further mechanistic and in vivo investigations.