A Novel Src Kinase Inhibitor, M475271, Inhibits VEGF-Induced Human Umbilical Vein Endothelial Cell Proliferation and Migration

Abstract

Abstract. 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 signalregulated kinase1/ 2 (ERK1 / 2) and p38 but not Akt activation in a concentration-dependent manner. M475271, PI3-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.

Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration

“…It was reported that increased p38 MAP kinase signaling was a feature of human and experimental diabetic nephropathy (Adhikary et al 2004). We have already reported that SB203580, a p38 MAP kinase inhibitor, suppressed cell migration induced by vascular endothelial growth factor in human umbilical vein endothelial cells (Ali et al 2005). In addition, consistent with our present findings, it has been reported that PDGF-induced p38 ffMAP kinase activation regulated cell migration in VSMCs K ISHIZAWA, N DORJSUREN and others .…”

Phosphatidylinositol Inhibits Vascular Endothelial Growth Factor-A– Induced Migration of Human Umbilical Vein Endothelial Cells

“…In the present study, PI at 30 µg / ml inhibited the Akt phosphorylation induced by VEGF-A, indicating that PI induces a direct and/ or upstream inhibition of Akt in the signaling cascade induced by VEGF-A. Ali et al (24) indicated that, the PI3K inhibitor LY294002 at 10 µM inhibits the VEGF-induced migration of HUVECs. Therefore, these results suggest that inhibition of phosphorylated-Akt inhibits the VEGF-A-induced migration.…”

Enhanced Effect of Connexin 43 on Cisplatin-Induced Cytotoxicity in Mesothelioma Cells

“…Tumors must undergo angiogenesis for survival and for metastatic spread in a limited physiological environment (30). Indeed, a previous report showed that a novel Src inhibitor, M475271, significantly inhibited VEGF-induced HUVEC proliferation, migration (31), and angiogenesis (32). It is, therefore, possible that Cx43 has a more suppressive role in growth and metastasis in vivo, where angiogenesis always contributes to tumor survival.…”