title: 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.affiliation: Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan.
authors.forename: Nermin
authors.initials: N
authors.lastname: Ali
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kanematsu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C503850:4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-((1-methyl-4-piperidinyl) methoxy); D015820:Cadherins; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D019061:src-Family Kinases