Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer

Abstract Castration-resistant prostate cancer (CRPC) continues to represent a critical therapeutic hurdle owing to its resistance to both androgen deprivation and next-generation antiandrogens like abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from Vitex agnus-castus , was identified as a potent inhibitor of AKR1C3. CAS showed potent inhibitory activity in enzymatic assays (IC₅₀ = 5.99 µM), significantly suppressed AKR1C3-mediated coumberone metabolism in 22Rv1 prostate cancer cells, and showed greater cytotoxicity in AKR1C3-expressing 22Rv1 cells relative to AKR1C3-deficient LNCaP cells. CAS significantly enhanced ABI’s cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31–0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. CAS enhanced apoptosis in ABI-treated 22Rv1 cells, as well as combination showed only a limited effect against normal epithelial PNT-2 cell line. Docking and molecular dynamics simulations indicated a stable CAS–AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC. Graphical Abstract