Yano Akihiro, Fujii Yasuhisa, Iwai Aki, Kageyama Yukio, Kihara Kazunori
Department of Urology, Tokyo Medical and Dental University, Yushima, Tokyo, Japan.
Clin Cancer Res. 2006 May 15;12(10):3003-9. doi: 10.1158/1078-0432.CCR-05-2085.
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).
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.
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.
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.
已知糖皮质激素，如泼尼松、氢化可的松和地塞米松，对激素难治性前列腺癌（HRPC）患者有一定临床益处。然而，糖皮质激素影响HRPC生长的潜在机制尚未完全明确。在此，我们假设糖皮质激素对HRPC的治疗作用可归因于通过糖皮质激素受体直接抑制血管生成，其机制是下调两个主要血管生成因子，即血管内皮生长因子（VEGF）和白细胞介素-8（IL-8）。
使用表达糖皮质激素受体的DU145细胞系，检测地塞米松对VEGF和IL-8表达以及细胞增殖的影响。通过分析VEGF和IL-8基因表达、微血管密度和肿瘤体积，确定地塞米松对DU145异种移植瘤的作用。
在常氧条件下，地塞米松分别使VEGF和IL-8基因表达显著下调50%（P < 0.001）和89%（P < 0.001），使VEGF和IL-8蛋白产生分别减少55%（P < 0.001）和74%（P < 0.001）。同样，氢化可的松也下调VEGF和IL-8基因表达。糖皮质激素受体拮抗剂RU486可完全逆转地塞米松的作用。即使在类似缺氧的条件下，地塞米松仍能抑制VEGF和IL-8表达。在DU145异种移植瘤中，地塞米松显著减小肿瘤体积、降低微血管密度并下调VEGF和IL-8基因表达，而地塞米松不影响细胞的体外增殖。
糖皮质激素可能通过体内糖皮质激素受体直接降低VEGF和IL-8的产生，抑制肿瘤相关血管生成，从而抑制雄激素非依赖性前列腺癌的生长。
