The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A.
The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A.
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DOI：
10.1186/1741-7015-8-19
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发表时间：
2010-03-24
期刊：
影响因子：
9.3
通讯作者：
North S
中科院分区：
文献类型：
--
作者：
Dedieu S;Canron X;Rezvani HR;Bouchecareilh M;Mazurier F;Sinisi R;Zanda M;Moenner M;Bikfalvi A;North S
Amifostine （WR-2721，以Ethyol®形式递送）是一种磷酸化的氨基硫醇化合物，在临床上与顺铂一起使用，以减少治疗对正常细胞的毒副作用，而不降低其对肿瘤细胞的疗效。其作用机制归因于其活性去磷酸化代谢物WR-1065的自由基清除特性。然而，氨磷汀也被描述为一种强效的模拟缺氧化合物和强p53诱导剂；已知这两种效应都能有效调节血管内皮生长因子（VEGF-A）的表达。这种药物的血管生成特性还没有明确的定义。为了研究(i)血管生成相关基因和蛋白质的表达以及（ii）药物对VEGF-A诱导的体外血管生成的影响，我们将癌细胞系和内皮细胞进行培养和氨磷汀处理。我们证明了用治疗剂量的WR-1065治疗几种人类癌细胞系导致不同的VEGF-A mRNA亚型的强烈诱导，而不依赖于HIF-1α。WR-1065对VEGF-A的诱导依赖于eIF2alpha/ATF4通路的激活。VEGF-A mRNA的上调伴随着VEGF-A蛋白的分泌增加，VEGF-A蛋白完全活跃于刺激血管内皮细胞（EC）。然而，用氨磷汀直接治疗EC损害了它们对外源性VEGF-A的反应能力，这一效应与VEGFR-2表达下调、VEGF-A细胞表面结合减少以及下游p42/44激酶磷酸化降低有关。综上所述，我们的研究结果表明，氨磷汀治疗通过两种明显相反的机制调节肿瘤血管生成——肿瘤细胞增加VEGF-A表达和抑制EC对VEGF-A刺激的反应能力。
Amifostine (WR-2721, delivered as Ethyol®) is a phosphorylated aminothiol compound clinically used in addition to cis-platinum to reduce the toxic side effects of therapeutic treatment on normal cells without reducing their efficacy on tumour cells. Its mechanism of action is attributed to the free radical scavenging properties of its active dephosphorylated metabolite WR-1065. However, amifostine has also been described as a potent hypoxia-mimetic compound and as a strong p53 inducer; both effects are known to potently modulate vascular endothelial growth factor (VEGF-A) expression. The angiogenic properties of this drug have not been clearly defined. Cancer cell lines and endothelial cells were used in culture and treated with Amifostine in order to study (i) the expression of angiogenesis related genes and proteins and (ii) the effects of the drug on VEGF-A induced in vitro angiogenesis. We demonstrated that the treatment of several human cancer cell lines with therapeutical doses of WR-1065 led to a strong induction of different VEGF-A mRNA isoforms independently of HIF-1α. VEGF-A induction by WR-1065 depends on the activation of the eIF2alpha/ATF4 pathway. This up-regulation of VEGF-A mRNA was accompanied by an increased secretion of VEGF-A proteins fully active in stimulating vascular endothelial cells (EC). Nevertheless, direct treatment of EC with amifostine impaired their ability to respond to exogenous VEGF-A, an effect that correlated to the down-regulation of VEGFR-2 expression, to the reduction in cell surface binding of VEGF-A and to the decreased phosphorylation of the downstream p42/44 kinases. Taken together, our results indicate that amifostine treatment modulates tumour angiogenesis by two apparently opposite mechanisms - the increased VEGF-A expression by tumour cells and the inhibition of EC capacity to respond to VEGF-A stimulation.
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影响因子：
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