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

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.

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

“…Therefore, considerable attention has been focused on the development of RAS blockade therapy as a new strategy for cancer treatment (8)(9)(10)(11)(12)(13)(14)(15)(16)30).…”

“…However, a number of reports exist on the concept of a localized RAS (tissue RAS) in various tissues. Angiotensin II type 1 (AT1) receptor has been also detected in carcinomas of the larynx, lung, liver, pancreas, kidney, bladder, prostate gland, breast, ovary, cervix, in malignant melanoma, and in sarcomas (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Lever et al reported the first clinical evidence that a long-term angiotensin II blockade might have a protective effect against carcinogenesis (17).…”

“…Lever et al reported the first clinical evidence that a long-term angiotensin II blockade might have a protective effect against carcinogenesis (17). There is increasing evidence that angiotensin II is involved in tumor biology and the potential anti-tumor effect of angiotensin II type 1 (AT1) receptor antagonist in tumors expressing AT1 receptor (8)(9)(10)(11)(12)(13)(14)(15)(16). Hence, the blockade of angiotensin II has been considered a noteworthy molecular targeted therapy in recent years.…”

“…It has been reported that angiotensin II induces tumor-angiogenesis via up-regulation of vascular endothelial growth factor (VEGF), and acts as a potent growth factor in some malignant tumors, including gastric cancer (11)(12)(13)(14)19). Although these findings suggest that angiotensin II could act as a key factor for tumor growth, the molecular mechanisms remain to be fully elucidated.…”

GPCRs and cancer

“…In this respect, ACE inhibitors and angiotensin II receptor blockers (ARBs) have recently acquired an increasing interest as chemopreventive agents [110,117,118] . Of note, ARBs have been associated with reduced cancer occurrence in patients with essential hypertension and a longer exposure to ARBs has been related with major benefits in cancer patients [119] .…”