Cis-dichlorodiammineplatinum Upregulates Angiotensin II Type 1 Receptors through Reactive Oxygen Species Generation and Enhances VEGF Production in Bladder Cancer

Abstract

We previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, and KU-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined AT1R and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had been treated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not changed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by scavenging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R antagonist significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment upregulated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expression though ROS generation and enhances VEGF production. Therefore, AT1R blockade may be an effective strategy for bladder cancer in combination with CDDP-based chemotherapy.