The Antipsychotic Aripiprazole Induces Cytotoxicity in Bladder Cancer Cells While Preserving Urothelial and Bladder Function.

Aripiprazole (ARI), an atypical antipsychotic, has demonstrated anticancer activity in several malignancies and may be a candidate for drug repurposing as an intravesical therapy for bladder cancer, particularly non-muscle-invasive bladder cancer (NMIBC). This study evaluated whether brief, intravesical-like ARI exposure could induce cytotoxic effects in bladder cancer cells while preserving normal bladder structure and function. RT4 and T24 bladder cancer cells, together with non-malignant UROtsa urothelial cells, were exposed to ARI (1-300 μM) for 30 min or 2 h, and viability was assessed at 24, 48 and 72 h. Reactive oxygen species (ROS) generation was measured in RT4 and T24 cells after 2 h pretreatment, while caspase-3 activity and stress-associated protein expression were examined in T24 cells. In parallel, an ex vivo porcine bladder model was used to assess the effects of luminal ARI pretreatment (300 μM, 2 h) on urothelial thickness, ATP and acetylcholine release, detrusor contractility, β-adrenergic relaxation, and nerve-evoked responses. ARI reduced viability in a concentration-dependent manner in RT4, T24 and UROtsa cells, with greater cytotoxicity after 2 h pretreatment. In bladder cancer cells, ROS increased only at higher concentrations, whereas ARI increased caspase-3 activity at lower concentrations and altered multiple stress-related proteins in T24 cells. In porcine bladder, ARI preserved urothelial structure and mediator release, maintained detrusor and neurogenic function, and enhanced the inhibitory influence attributed to urothelium-derived inhibitory factor (UDIF). Collectively, these findings identify ARI as a mechanistically active yet bladder-sparing candidate for intravesical repurposing and support its further evaluation as a potential therapy for bladder cancer.