A novel Src kinase inhibitor, M475271, inhibits VEGF-induced human umbilical vein endothelial cell proliferation and migration.

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 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.

• Authors: Nermin Ali, Masanori Yoshizumi, Yoshiko Fujita, Yuki Izawa, Yasuhisa Kanematsu, Keisuke Ishizawa, Koichiro Tsuchiya, Seiji Yano, Saburo Sone, Toshiaki Tamaki
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 98 Issue 2 Pg. 130-41 (Jun 2005) ISSN: 1347-8613 [Print] Japan
• PMID: 15937404 (Publication Type: Journal Article)

Chemical References

• 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-((1-methyl-4-piperidinyl) methoxy)
• Enzyme Inhibitors
• Piperidines
• Quinazolines
• Vascular Endothelial Growth Factor A
• src-Family Kinases
• Mitogen-Activated Protein Kinases

Topics

• Cell Line
• Cell Movement (physiology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Endothelium, Vascular (cytology, drug effects, enzymology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Phosphorylation
• Piperidines (pharmacology)
• Quinazolines (pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, physiology)
• src-Family Kinases (antagonists & inhibitors)