Autophagy Plays a Suppressive Role in Bladder Tumor Formation in an Orthotopic Mouse Model and Bladder Cancer Patient Specimens.

Autophagy plays either a suppressing or promoting role during tumor development. Clarifying the role of autophagy in bladder tumorigenesis both in vitro and in vivo is crucial for developing novel therapeutic strategies through manipulating autophagy activity. Herein, we noninvasively monitored how autophagy affects bladder tumor formation using a murine model of orthotopic bladder tumor formation by "in vivo imaging system (IVIS) and transabdominal micro-ultrasound imaging (MUI)" and validated the notion in cell lines and bladder cancer patients. Mimic clinical administration, all the drugs were delivered into the urinary bladder of the mice via intravesical instillation. Plasma biochemistry parameters, hemograms, blood pressure, and blood concentration of amiodarone and desethylamiodarone were analyzed in treated mice. Low autophagy activity was detected in the bladder tumors and associated with poor overall survival of bladder cancer patients. Amiodarone-induced autophagy activity suppressed bladder tumor formation, whereas silencing Atg5 expression reversed the suppression. Notably, amiodarone showed equivalent anti-tumor efficacy but with fewer side effects on the treated mice compared to the clinical anti-cancer drug Mitomycin C (MMC). Furthermore, amiodarone delivered by intravesical route showed a negligible influence on the physiologic conditions of the treated mice. Our orthotopic mouse model revealed that increasing autophagy activity alleviated bladder tumor development. Similarly, low autophagy is associated with a poor overall survival rate. Furthermore, repurposing amiodarone-induced autophagy accompanied by trivial side effects shows potential for the treatment of bladder cancer patients.