Sanguinarine chloride exerts its antitumor effects on enzalutamide-resistant prostate cancer by inhibiting cell proliferation and promoting senescence via targeting AR signaling.

OBJECTIVE: Prostate cancer (PCa) remains a leading cause of cancer-associated morbidity among men globally. Although enzalutamide (ENZ), a second-generation androgen receptor (AR) antagonist, serves as a mainstay therapy for castration-resistant prostate cancer (CRPC), therapeutic resistance inevitably emerges. This underscores an urgent demand for innovative treatment strategies. METHODS: CCK-8, colony formation, EdU staining, flow cytometry, Hoechst 33,258 staining, western blotting, proteomics analysis, and senescence-associated β-galactosidase (SA-β-gal) staining were performed to reveal the role and underlying mechanisms of S.C in ENZ-resistant prostate cancer. Target prediction, molecular docking, and cellular thermal shift assay (CETSA) were used to identify the target of S.C. Finally, the impact of S.C in vivo was evaluated using ENZ-resistant xenograft models. RESULTS: Our results showed that S.C effectively suppresses cell viability in ENZ-resistant models through the dual induction of apoptosis and cellular senescence. Database mining, molecular docking, and CETSA identified AR as a putative target of S.C, which was subsequently validated in vivo. S.C treatment significantly inhibited the AR signaling pathway and suppressed tumor growth in ENZ-resistant xenograft models. CONCLUSION: To our knowledge, this study demonstrates that S.C could be a promising multi-mechanistic agent which can overcome ENZ resistance by targeting AR and inducing two distinct cell death pathways, offering a potential novel therapeutic strategy for CRPC.