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

Journal of Pharmacological Sciences

Masanori Yoshizumi²  Nermin Ali²  Yoshiko Fujita²  Saburo Sone¹  Toshiaki Tamaki²  Yuki Izawa²  Seiji Yano¹  Keisuke Ishizawa²  Koichiro Tsuchiya³  Yasuhisa Kanematsu² 

[1]Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School Institute of Health Biosciences

[2]Department of Pharmacology, The University of Tokushima Graduate School Institute of Health Biosciences

[3]Department of Clinical Pharmacology, The University of Tokushima Graduate School Institute of Health Biosciences

关键词: M475271;    vascular endothelial growth factor;    human umbilical vein endothelial cell proliferation and migration;    angiogenesis;   

DOI  :  10.1254/jphs.FP0040850

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(43)Cited-By(12)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, [3H]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, 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.

【 授权许可】

Unknown