biostudies-literatureBai LNational Cancer InstituteNational Institute on Minority Health and Health DisparitiesU.S. Department of Education101707https://www.ebi.ac.uk/biostudies/studies/S-EPMC10248552biostudies-literatureUnknown34Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affecteTranslational oncologyBromocriptine monotherapy overcomes prostate cancer chemoresistance in preclinical models.PMC102485525U54MD007590R01CA256058R42CA217491White EZHinton CVLi DWu AYDu YWu DLi XCook NYang YZhao RFu HBai LDanaher ABowen NJKucuk OQui MfalseBromocriptine monotherapy overcomes prostate cancer chemoresistance in preclinical models.Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affecte2023-01-01T00:00:00Z2023 Jun2025-04-27T02:19:11.165Z2025-04-06T18:31:05.09ZS-EPMC102485523727112110.1016/j.tranon.2023.101707