Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

• Published in: Clinical cancer research 2006-05, Vol.12 (10), p.3003-3009
• Main Authors: YANO, Akihiro, FUJII, Yasuhisa, IWAI, Aki, KAGEYAMA, Yukio, KIHARA, Kazunori
• Format: Article
• Language: English
• Subjects: angiogenesis; angiogenesis and microcirculation; angiogenesis inhibitors: endogenous and synthetic; angiogenic factors and receptors; Animals; Antineoplastic agents; Biological and medical sciences; Cell Hypoxia; Cell Proliferation - drug effects; Dexamethasone - pharmacology; Down-Regulation; Gene Expression Profiling; genitourinary cancers: prostate; glucocorticoid; Glucocorticoids - pharmacology; Gynecology. Andrology. Obstetrics; Humans; interleukin-8; Interleukin-8 - biosynthesis; Male; Male genital diseases; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Polymerase Chain Reaction; prostate cancer; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Receptors, Glucocorticoid - drug effects; Receptors, Glucocorticoid - physiology; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - drug effects
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2085

Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% ( P < 0.001) and 89% ( P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% ( P < 0.001) and 74% ( P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo .