The Novel Src Kinase Inhibitor M475271 Inhibits VEGF-Induced Vascular Endothelial-Cadherin and β-Catenin Phosphorylation but Increases Their Association

Journal of Pharmacological Sciences

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

[2]Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan

[3]Department of Pharmacology, Nara Medical University School of Medicine, Japan

[4]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