Angiotensin II Type 1 Receptor Antagonist Candesartan as an Angiogenic Inhibitor in a Xenograft Model of Bladder Cancer

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Abstract
Purpose: There have been several studies on the antitumor activity of angiotensin II type 1 receptor (AT1R) antagonists. In this study, we evaluated the efficacy of the AT1R antagonist candesartan in bladder cancer. Experimental Design: For the study in vitro, human bladder cancer cells (KU-19-19) were cultured with or without angiotensin II and candesartan. Various cytokines and cell viability were analyzed. For the study in vivo, a tumor xenograft model was prepared in nude mice using KU-19-19 cells. Mice were given candesartan daily by oral gavage. Microvessel density, expression of vascular endothelial growth factor (VEGF), and apoptosis were assessed. Results: Candesartan did not induce direct toxicity in KU-19-19 cells, but VEGF and interleukin-8 were significantly lower in candesartan-treated cells (2.55 ± 0.25 and 6.58 ± 0.48 pg/103 cells) than in the angiotensin II–treated control cells (3.16 ± 0.42 and 7.91 ± 0.69 pg/103 cells). In mice, candesartan both at doses of 2 and 10 mg/kg/d significantly suppressed tumor growth in mice (35.4% and 33.5% reduction in tumor volume). Microvessel density was significantly decreased by candesartan (9.8 ± 2.8 per field) compared with the control group (17.6 ± 6.0 per field), and VEGF expression was significantly suppressed by this AT1R antagonist. However, candesartan did not induce apoptosis of cancer cells in the tumor. Conclusions: Specific blockade of AT1R prevented bladder tumor growth by inhibiting angiogenesis. However, its antitumor effect was not due to direct toxicity. Because AT1R antagonists are widely used to treat hypertension, and a 2 mg/kg/d dose level of candesartan is clinically achievable, this AT1R antagonist could also be used to treat bladder cancer.