Angiotensin II Type 1 Receptor Antagonist Enhances Cis-dichlorodiammineplatinum-Induced Cytotoxicity in Mouse Xenograft Model of Bladder Cancer

Objectives: To examine whether candesartan enhances the cytotoxicity of cis-dichlorodiammineplatinum (CDDP) in mice with bladder cancer as a method to enhance the therapeutic effects of CDDP. CDDP is an antitumor agent conventionally used against bladder cancer; however, its therapeutic efficacy appears to not be fully satisfactory. Recent studies have shown the antitumor activity of the angiotensin II type 1 receptor antagonist candesartan. Methods: A xenograft model was prepared in nude mice using human bladder cancer cells (KU-19-19). Candesartan (1 mg/kg/d) was administered daily by oral gavage from the day of implantation plus 28 days, and CDDP (1 mg/kg/d) was administered intraperitoneally from days 5 to 9. The microvessel density, vascular endothelial growth factor expression, and apoptosis were investigated immunohistochemically. Results: Candesartan, CDDP, and candesartan-CDDP suppressed tumor growth to 41.9%, 33.8%, and 13.2%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared with each single agent alone. The microvessel density was significantly decreased in the candesartan and candesartan-CDDP groups compared with the control group. Vascular endothelial growth factor expression was significantly decreased in the candesartan, CDDP, and candesartan-CDDP groups compared with the control group. The apoptotic index was significantly increased in the CDDP and candesartan-CDDP groups compared with the control and candesartan groups. Conclusions: It is quite likely that candesartan and CDDP suppressed tumor growth by inhibiting angiogenesis and inducing apoptosis, respectively. Furthermore, combined treatment with candesartan enhanced CDDP-induced cytotoxicity by further suppressing angiogenesis. These results suggest that candesartan could be a candidate for innovational therapy of bladder cancer.