A novel Src kinase inhibitor, M475271, inhibits VEGF-induced human umbilical vein endothelial cell proliferation and migration.
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, 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.
Ali
Nermin
N
Department of Pharmacology, The University of Tokushima Graduate School Institute of Health Biosciences, Japan.
Yoshizumi
Masanori
M
Fujita
Yoshiko
Y
Izawa
Yuki
Y
Kanematsu
Yasuhisa
Y
Ishizawa
Keisuke
K
Tsuchiya
Koichiro
K
Yano
Seiji
S
Sone
Saburo
S
Tamaki
Toshiaki
T
D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C503850:4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-((1-methyl-4-piperidinyl) methoxy); D004791:Enzyme Inhibitors; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases