The novel Src kinase inhibitor M475271 inhibits VEGF-induced vascular endothelial-cadherin and beta-catenin phosphorylation but increases their association.
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.
Ali
Nermin
N
Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan.
Yoshizumi
Masanori
M
Yano
Seiji
S
Sone
Saburo
S
Ohnishi
Hideki
H
Ishizawa
Keisuke
K
Kanematsu
Yasuhisa
Y
Tsuchiya
Koichiro
K
Tamaki
Toshiaki
T
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*
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