Efficacy and Safety of Resveratrol in the Treatment of Bladder Cancer Derived Organoids

Abstract Intravesical instillation is a prevalent approach in bladder cancer (BC) management, yet it often causes adverse reactions and drug resistance. Safer and more effective alternative is therefore in urgent need, and resveratrol (RES) emerges as a promising candidate. However, the effectiveness of RES against BC remains unexplored. In this study, BC‐derived organoids (BCOs) are established to evaluate the efficacy of RES in comparison to conventional anti‐BC drugs (epirubicin (EPI), cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR)). After a 96‐h treatment, RES demonstrates superior anti‐BCOs efficacy (64.00%; 16/25) compared to the other chemotherapeutics (15.38% to 53.85%). Eighteen BCOs are treated with RES, EPI, or a combination of RES and EPI (RES/EPI) in short‐term (3 h per day for four times) to mimic intravesical instillation. RES exhibits the stronger efficacy (44.44%; 8/18) than EPI against BCOs, and the RES/EPI enhances sensitivity of a single drug (50.00%; 9/18). RES inhibits the activation of β‐catenin/CD44 axis in RES‐sensitive BCOs. The organoid‐forming potential of mouse bladder is preserved after intravesical instillation of RES, and 200 × 10 −6 m RES demonstrates no adverse effects on patient‐derived bladder urothelial organoids. The findings highlight the potential of RES, particularly in combination with EPI, to improve intravesical instillation outcomes in BC management.