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Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in prostate cancer
Author(s) -
Kosaka Takeo,
Miyajima Akira,
Takayama Eiji,
Kikuchi Eiji,
Nakashima Jun,
Ohigashi Takashi,
Asano Tomohiko,
Sakamoto Michiie,
Okita Hajime,
Murai Masaru,
Hayakawa Masamichi
Publication year - 2006
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20486
Subject(s) - candesartan , lncap , angiotensin ii , endocrinology , prostate cancer , angiogenesis , medicine , androgen receptor , androgen , cancer research , blockade , receptor , cancer , hormone
BACKGROUND Angiotensin II (AII) type 1 receptor (AT1R) antagonists are used widely as antihypertensive agents, and long‐term AT1R blockade may have a protective effect against cancer. We previously demonstrated that specific AT1R blockade with candesartan, an AT1R antagonist, inhibited vascular endothelial growth factor (VEGF) production and dramatically decreased lung metastasis of renal cancer by inhibiting tumor angiogenesis. This study was then undertaken to investigate the effects of AT1R blockade using candesartan in prostate cancer (PCa). METHODS We first determined whether hormone‐independence is associated with tumor angiogenesis and AT1R expression. Accordingly, we postulated that AT1R blockade may affect angiogenesis in androgen‐independent PCa rather than in androgen‐dependent PCa, and investigated the effects of AII and candesartan on PCa cell lines and a tumor xenograft model. RESULTS A human hormone‐refractory PCa (HRPC) and C4‐2 androgen‐independent PCa cell line showed significantly higher expression of VEGF, MVD, and AT1R than did human androgen‐dependent PCa and an LNCaP androgen‐dependent PCa cell line. In vitro, AII and candesartan did not directly affect the proliferation of LNCaP and C4‐2 cells, but candesartan significantly suppressed VEGF production in C4‐2 cells. In vivo, candesartan significantly suppressed VEGF expression, serum PSA concentration and tumor growth (1.1 ± 0.2, 45.0 ± 17.6 ng/ml, 235.8 ± 37.4 mm 3 ) in C4‐2 xenografts in castrated mice, compared with the controls (2.4 ± 0.6, 376.7 ± 74.2 ng/ml, 830.8 ± 147.6 mm 3 ). CONCLUSIONS Candesartan exerted preventive effects on HRPC, rather than on androgen‐sensitive PCa, through the inhibition of tumor angiogenesis. Prostate 67:41–49, 2007. © 2006 Wiley‐Liss, Inc.