Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer
Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer
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DOI：
10.1158/1078-0432.ccr-05-2213
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发表时间：
2006-05-01
影响因子：
11.5
通讯作者：
Murai, M
中科院分区：
文献类型：
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作者：
Kosugi, M;Miyajima, A;Murai, M
目的：血管紧张素II 1型受体(AT1R)拮抗剂的抗肿瘤活性已有多项研究。在本研究中，我们评估了AT1R拮抗剂坎地沙坦对膀胱癌的疗效。实验设计：体外培养人膀胱癌细胞(KU-19-19)，加入或不加入血管紧张素11和坎地沙坦。分析各种细胞因子和细胞存活率。为了进行体内研究，用KU-19-19细胞建立了裸鼠移植瘤模型。小鼠每天口服坎地沙坦。结果：坎地沙坦对KU-19-19细胞无直接毒性作用，但血管内皮生长因子和白介素8水平显著低于血管紧张素II对照组(3.16+/-0.42和7.91+/-0.69 pg/10(3)细胞)。在小鼠中，坎地沙坦2和10 mg/kg/d剂量均显著抑制小鼠肿瘤生长(肿瘤体积分别减少35.4%和33.5%)。坎地沙坦组微血管密度(9.8+/-2.8个/视野)显著低于对照组(17.6+/-6.0个/视野)，该AT1R拮抗剂显著抑制血管内皮生长因子的表达。结论：特异性阻断AT1R可能通过抑制血管生成来抑制膀胱癌的生长，但其抗肿瘤作用并非直接毒性作用。由于AT1R拮抗剂被广泛用于治疗高血压，而坎地沙坦的剂量水平在临床上是可以达到的，这种AT1R拮抗剂也可以用于治疗膀胱癌。
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 11 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/10(3) cells) than in the angiotensin II-treated control cells (3.16 +/- 0.42 and 7.91 +/- 0.69 pg/10(3) 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.