Antiangiogenic and vascular-targeting activity of the microtubule-destabilizing trans-resveratrol derivative 3,5,4′-trimethoxystilbene
Antiangiogenic and vascular-targeting activity of the microtubule-destabilizing trans-resveratrol derivative 3,5,4′-trimethoxystilbene
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DOI：
10.1124/mol.104.009043
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发表时间：
2005-05-01
影响因子：
3.6
通讯作者：
Presta, M
中科院分区：
文献类型：
--
作者：
Belleri, M;Ribatti, D;Presta, M
新生血管在肿瘤和血管增生性疾病中起重要作用。迄今为止，已经开发了两种主要方式来影响新血管形成：通过抗血管生成化合物来预防新血管形成，以及通过血管靶向剂来破坏未成熟血管。反式白藜芦醇，发现在葡萄和葡萄酒，发挥抗氧化剂，维生素C，和抗血管生成的活动。这里，在所测试的各种合成的反式白藜芦醇衍生物中，3，5，4 ′-三甲氧基芪是一种抗血管生成剂，在抑制内皮细胞增殖、发芽、胶原凝胶侵入和形态发生方面比母体化合物强30至100倍（ID 50 = 0.3-3.0 μ M）。此外，3，5，4 '-三甲氧基芪通过引起微管分解和微管蛋白解聚以及通过损害微管组织中心的重新定位和迁移内皮细胞中膜皱褶的形成而充当血管靶向剂。与血管靶向能力一致，在离体大鼠主动脉环测定中，3，5，4 '-三甲氧基芪仅在亚融合内皮细胞中诱导凋亡，并诱导未成熟血管的凋亡消退。在体内，3，5，4 '-三甲氧基二苯乙烯可引起斑马鱼胚胎躯干部血流迅速停滞和节间血管退化。此外，它抑制血管生长，并导致鸡胚血管区原有血管消失。总之，3，5，4 '-三甲氧基芪将抗血管生成特征与显著的血管靶向活性相关联。
Neovascularization plays an important role in neoplasia and angioproliferative diseases. Two major modalities have been developed so far to affect neovascularization: its prevention by antiangiogenic compounds, and immature vessel disruption by vascular-targeting agents. trans-Resveratrol, found in grapes and wine, exerts antioxidant, antineoplastic, and antiangiogenic activities. Here, among various synthetic trans-resveratrol derivatives tested, 3,5,4'-trimethoxystilbene was an antiangiogenic agent 30 to 100 times more potent than parent compound in inhibiting endothelial cell proliferation, sprouting, collagen gel invasion, and morphogenesis (ID50 = 0.3-3.0 mu M). In addition, 3,5,4'-trimethoxystilbene acts as a vascular-targeting agent by causing microtubule disassembling and tubulin depolymerization and by impairing the repositioning of the microtubule organization center and the formation of membrane ruffles in migrating endothelial cells. In keeping with a vascular-targeting ability, 3,5,4'-trimethoxystilbene induced apoptosis only in subconfluent endothelial cells and apoptotic regression of immature vessels in the ex vivo rat aorta ring assay. In vivo, 3,5,4'-trimethoxystilbene caused the rapid stasis of blood flow and regression of intersegmental vessels in the trunk of zebrafish embryos. In addition, it inhibited blood vessel growth and caused the disappearance of pre-existing blood vessels in the area vasculosa of the chick embryo. In conclusion, 3,5,4'-trimethoxystilbene associates an antiangiogenic profile to a significant vascular-targeting activity.