Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer

Takeo Kosaka, Akira Miyajima, Eiji Takayama, Eiji Kikuchi, Jun Nakashima, Takashi Ohigashi, Tomohiko Asano, Michiie Sakamoto, Hajime Okita, Masaru Murai, Masamichi Hayakawa

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalProstate
Volume67
Issue number1
DOIs
Publication statusPublished - 2007 Jan

Fingerprint

Angiotensin I
Angiogenesis Inhibitors
Angiotensin Receptor Antagonists
Prostatic Neoplasms
Androgens
Vascular Endothelial Growth Factor A
Hormones
Neoplasms
Heterografts
Angiotensin II
Angiotensin II Type 1 Receptor Blockers
Cell Line
Kidney Neoplasms
candesartan
Tumor Cell Line
Antihypertensive Agents
Neoplasm Metastasis
Lung

Keywords

  • Angiotensin II
  • Hormone
  • Prostate cancer
  • Refractory

ASJC Scopus subject areas

  • Urology

Cite this

Kosaka, T., Miyajima, A., Takayama, E., Kikuchi, E., Nakashima, J., Ohigashi, T., ... Hayakawa, M. (2007). Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer. Prostate, 67(1), 41-49. https://doi.org/10.1002/pros.20486

Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer. / Kosaka, Takeo; Miyajima, Akira; Takayama, Eiji; Kikuchi, Eiji; Nakashima, Jun; Ohigashi, Takashi; Asano, Tomohiko; Sakamoto, Michiie; Okita, Hajime; Murai, Masaru; Hayakawa, Masamichi.

In: Prostate, Vol. 67, No. 1, 01.2007, p. 41-49.

Research output: Contribution to journalArticle

Kosaka, T, Miyajima, A, Takayama, E, Kikuchi, E, Nakashima, J, Ohigashi, T, Asano, T, Sakamoto, M, Okita, H, Murai, M & Hayakawa, M 2007, 'Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer', Prostate, vol. 67, no. 1, pp. 41-49. https://doi.org/10.1002/pros.20486
Kosaka T, Miyajima A, Takayama E, Kikuchi E, Nakashima J, Ohigashi T et al. Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer. Prostate. 2007 Jan;67(1):41-49. https://doi.org/10.1002/pros.20486
Kosaka, Takeo ; Miyajima, Akira ; Takayama, Eiji ; Kikuchi, Eiji ; Nakashima, Jun ; Ohigashi, Takashi ; Asano, Tomohiko ; Sakamoto, Michiie ; Okita, Hajime ; Murai, Masaru ; Hayakawa, Masamichi. / Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer. In: Prostate. 2007 ; Vol. 67, No. 1. pp. 41-49.
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AU - Nakashima, Jun

AU - Ohigashi, Takashi

AU - Asano, Tomohiko

AU - Sakamoto, Michiie

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AB - 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.

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