The Novel Src Kinase Inhibitor M475271 Inhibits VEGF-Induced Vascular Endothelial-Cadherin and β-Catenin Phosphorylation but Increases Their Association
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概要
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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.
著者
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Tamaki Toshiaki
Department Of Pharmacology Kagawa Medical School
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Kanematsu Yasuhisa
Department Of Pharmacology Institute Of Health Biosciences The University Of Tokushima Graduate Scho
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Ali Nermin
Department Of Pharmacology The University Of Tokushima Graduate School Institute Of Health Bioscienc
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Yoshizumi Masanori
Department Of Pharmacology Nara Medical University School Of Medicine
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Ishizawa Keisuke
Department Of Medical Pharmacology Institute Of Health Biosciences The University Of Tokushima Gradu
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Yano Seiji
Department Of Internal Medicine And Molecular Tharapeutics University Of Tokushima School Of Medicin
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Tsuchiya Koichiro
Department Of Cardiovascular Surgery The University Of Tokushima Graduate School Of Health Bioscienc
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Ohnishi Hideki
Department Of Gastroenterology And Hepatology Okayama University Graduate School Of Medicine Dentistry And Pharmaceutical Sciences
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SONE Saburo
Department of Internal Medicine and Molecular Tharapeutics, University of Tokushima School of Medicine
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Ohnishi Hideki
Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan
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Ali Nermin
Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan
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Tamaki Toshiaki
Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan
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Ishizawa Keisuke
Department of Pharmacology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan
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