The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis
The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis
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DOI：
10.1158/0008-5472.can-07-5809
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
--
作者：
Heckman, Caroline A.;Holopainen, Tanja;Alitalo, Kari
实体瘤表达了维持其生长和促进其传播所需的一系列因素。其中包括血管内皮生长因子- a (VEGF-A)，它是血管生成的关键刺激物，VEGF-C是淋巴管生成的主要介质。小分子酪氨酸激酶抑制剂提供了抑制多种激酶的潜力，并通过多种机制阻碍肿瘤生长。然而，它们对个体目标的效力可能有所不同。Cediranib （RECENTIN; AZD2171）是一种VEGF信号抑制剂，在实验模型中已被证明可以阻止VEGF- a诱导的血管生成和原发性肿瘤生长，但Cediranib对VEGF受体(VEGFR)-3介导的内皮细胞功能和淋巴管生成的影响尚不清楚。为了更好地了解cediranib对VEGFR-3的活性及其与VEGFR-2活性的相关信号事件，我们使用了受体特异性配体VEGF-E和VEGF-C156S。在人内皮细胞中，cediranib抑制vegf - e诱导的VEGFR-2磷酸化和vegf - c156s诱导的VEGFR-3磷酸化
Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of