The novel Src kinase inhibitor M475271 inhibits VEGF-induced vascular endothelial-cadherin and β-catenin phosphorylation but increases their association
The novel Src kinase inhibitor M475271 inhibits VEGF-induced vascular endothelial-cadherin and β-catenin phosphorylation but increases their association
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DOI：
10.1254/jphs.fp0060357
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发表时间：
2006-09-01
影响因子：
3.5
通讯作者：
Tamaki, Toshiaki
中科院分区：
文献类型：
--
作者：
Ali, Nermin;Yoshizumi, Masanori;Tamaki, Toshiaki
M475271，4-喹唑烷胺，N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)甲氧基]-(9Cl)，是一种新的苯胺喹唑啉衍生物，在体内具有选择性地抑制Src激酶活性和肿瘤生长的作用。血管内皮生长因子(VEGF)诱导的血管生成在肿瘤的生长和转移中起着关键作用。血管内皮细胞(VE)-钙粘附素是一种内皮细胞特异性的黏附分子，可通过β-连环蛋白等多种锚定分子与细胞骨架相互作用。在这里，我们研究了M475271对VE-钙粘附素和β-连环素磷酸化和结合的影响。我们还检测了其对血管内皮生长因子诱导的人脐静脉内皮细胞(HUVEC)增殖、迁移和管状形成的影响。结果显示，M475271可显著抑制血管内皮生长因子诱导的VE-钙粘附素和β-连环素的磷酸化。然而，与血管内皮生长因子治疗组相比，M475271显著增加了VE-钙粘附素和β-连环素的关联性。激光共聚焦显微镜检查证实M475271对VE-钙粘蛋白和β-连环蛋白结合的增强作用。最后，M475271对血管内皮生长因子诱导的HUVEC的增殖、迁移和管状形成的抑制作用与PP2和除草剂A相当。这些发现表明，M475271通过维持细胞-细胞连接的稳定性来抑制血管生成。虽然不能排除其他信号分子的参与，但M475271有潜力作为一种药物来抑制肿瘤生长和转移所需的血管生成。
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.