dichlorodiammineplatinum Upregulates Angiotensin II e 1 Receptors through Reactive Oxygen Species eration and Enhances VEGF Production

ownload previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of hlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic nism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect ulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, U-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had reated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was signifiupregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not ed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, U-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by ging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R anst significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment lated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cysy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression orresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expresthan c sion thoughROSgeneration and enhancesVEGFproduction. Therefore,AT1Rblockademaybe an effective strategy for bladder cancer in combinationwith CDDP-based chemotherapy.Mol Cancer Ther; 9(11); OF1–11. ©2010 AACR.