The novel Src kinase inhibitor M475271 inhibits VEGF-induced vascular endothelial-cadherin and beta-catenin phosphorylation but increases their association.

Abstract

M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that displays selective inhibition of Src kinase activity and tumor growth in vivo. Vascular endothelial growth factor (VEGF)-induced angiogenesis plays a pivotal role in tumor growth and metastasis. Vascular endothelial (VE)-cadherin is an endothelial cell-specific adhesion molecule that can interact with the cytoskeleton via several anchoring molecules such as beta-catenin. Here, we examined the effect of M475271 on VE-cadherin and beta-catenin phosphorylation and association. We also examined its effect on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. The findings reveal pretreatment with M475271 significantly inhibits VEGF-induced VE-cadherin and beta-catenin phosphorylation. However, M475271 significantly increases VE-cadherin and beta-catenin association compared to the VEGF-treated group. Confocal laser microscopic examination confirmed the augmentation effect of M475271 on VE-cadherin and beta-catenin association. Finally, M475271 was shown to have inhibitory effects comparable to those of PP2 and Herbimycin A on VEGF-induced HUVEC proliferation, migration, and tube formation. These findings suggest that M475271 attenuates VEGF-induced angiogenesis by maintaining cell-cell junction stability. Although the involvement of other signaling molecules cannot be ruled out, M475271 has potential as a drug for the inhibition of the angiogenesis needed for tumor growth and metastasis.

• Authors: Nermin Ali, Masanori Yoshizumi, Seiji Yano, Saburo Sone, Hideki Ohnishi, Keisuke Ishizawa, Yasuhisa Kanematsu, Koichiro Tsuchiya, Toshiaki Tamaki
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 102 Issue 1 Pg. 112-20 (Sep 2006) ISSN: 1347-8613 [Print] Japan
• PMID: 16974068 (Publication Type: Journal Article)

Chemical References

• 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-((1-methyl-4-piperidinyl) methoxy)
• Cadherins
• Piperidines
• Quinazolines
• Vascular Endothelial Growth Factor A
• beta Catenin
• src-Family Kinases

Topics

• Cadherins (metabolism, physiology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Electrophoresis, Polyacrylamide Gel
• Endothelium, Vascular (drug effects, metabolism)
• Humans
• Intercellular Junctions (drug effects)
• Microscopy, Confocal
• Neovascularization, Physiologic (drug effects, physiology)
• Phosphorylation
• Piperidines (pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects, physiology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, pharmacology)
• beta Catenin (metabolism, physiology)
• src-Family Kinases (antagonists & inhibitors)