Journal of Pharmacological Sciences | |
The Novel Src Kinase Inhibitor M475271 Inhibits VEGF-Induced Vascular Endothelial-Cadherin and β-Catenin Phosphorylation but Increases Their Association | |
Masanori Yoshizumi3  Nermin Ali1  Saburo Sone2  Toshiaki Tamaki1  Hideki Ohnishi1  Seiji Yano2  Keisuke Ishizawa1  Koichiro Tsuchiya4  Yasuhisa Kanematsu1  | |
[1] Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan;Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan;Department of Pharmacology, Nara Medical University School of Medicine, Japan;Department of Clinical Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan | |
关键词: M475271; vascular endothelial growth factor; vascular endothelial-cadherin; β-catenin; angiogenesis; | |
DOI : 10.1254/jphs.FP0060357 | |
学科分类:药学 | |
来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society | |
【 摘 要 】
References(37)Cited-By(7)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 β-catenin. Here, we examined the effect of M475271 on VE-cadherin and β-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 β-catenin phosphorylation. However, M475271 significantly increases VE-cadherin and β-catenin association compared to the VEGF-treated group. Confocal laser microscopic examination confirmed the augmentation effect of M475271 on VE-cadherin and β-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.
【 授权许可】
Unknown
【 预 览 】
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