Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in prostate cancer.
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.
Kosaka
Takeo
T
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Miyajima
Akira
A
Takayama
Eiji
E
Kikuchi
Eiji
E
Nakashima
Jun
J
Ohigashi
Takashi
T
Asano
Tomohiko
T
Sakamoto
Michiie
M
Okita
Hajime
H
Murai
Masaru
M
Hayakawa
Masamichi
M
D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013777:Tetrazoles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D020533:Angiogenesis Inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan