A novel src kinase inhibitor, m475271, inhibits VEGF-induced human umbilical vein endothelial cell proliferation and migration
A novel src kinase inhibitor, m475271, inhibits VEGF-induced human umbilical vein endothelial cell proliferation and migration
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DOI：
10.1254/jphs.fp0040850
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Tamaki, T
中科院分区：
文献类型：
--
作者：
Ali, N;Yoshizumi, M;Tamaki, T
据报道，血管内皮生长因子（VEGF）是一种有效的促血管生成因子，在生理性和病理性血管生成中都起着关键作用。m475271,4 -喹唑啉胺，N-（2-氯-5-甲氧基苯基）-6-甲氧基-7-[（1-甲基-4-哌替啶基）甲氧基]-(9Cl)是一种新的苯胺类喹唑啉衍生物，在体内表现出选择性抑制Src激酶活性和肿瘤生长的作用。在这里，我们研究了M475271对vegf诱导的人脐静脉内皮细胞（HUVEC）增殖和迁移的影响及其细胞内机制。我们的研究结果表明，M475271预处理可显著抑制vegf诱导的HUVEC增殖、[3 H]胸苷结合和迁移。M475271抑制vegf诱导的Flk-1和Src磷酸化及其关联。共聚焦激光显微镜检查证实M475271对vegf诱导的Flk-1/Src关联有抑制作用。M475271以浓度依赖性的方式抑制vegf诱导的细胞外信号调节激酶1/2 （ERK1/2）和p38，但不抑制Akt的激活。M475271、P13-K抑制剂和p38抑制剂抑制vegf诱导的HUVEC增殖和迁移。然而，MEK1/2抑制剂抑制vegf诱导的增殖，但不抑制迁移。这些发现表明，M475271通过抑制Src、ERK1/2和/或p38信号通路，减弱vegf诱导的HUVEC增殖和迁移。综上所述，这些数据表明M475271可能是抑制内皮细胞增殖和血管生成相关迁移的有用候选药物。
Vascular endothelial growth factor (VEGF) was reported to be a potent proangiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that showed selective inhibition of Src kinase activity and tumor growth in vivo. Here, we examined the effect of M475271 on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration and their intracellular mechanisms. Our findings showed that M475271 pretreatment resulted in a significant inhibition of VEGF-induced HUVEC proliferation, [3 H]thymidine incorporation, and migration. M475271 inhibited VEGF-induced Flk-1 and Src phosphorylation and their association. Confocal laser microscopic examination confirmed the inhibitory effect of M475271 on VEGF-induced Flk-1/Src association. M475271 inhibited VEGF-induced extracellular signal-regulated kinase1/2 (ERK1/2) and p38 but not Akt activation in a concentration-dependent manner. M475271, P13-K inhibitor, and p38 inhibitor inhibited VEGF-induced HUVEC proliferation and migration. However, a MEK1/2 inhibitor inhibited VEGF-induced proliferation but not migration. These findings suggest that M475271 attenuates VEGF-induced HUVEC proliferation and migration through the inhibition of signaling pathways involving Src, ERK1/2, and/or p38. Taken together, these data indicate that M475271 may be a useful candidate for inhibition of endothelial cell proliferation and migration relevant to angiogenesis.