Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells
Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells
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DOI：
10.1097/00001813-200603000-00005
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发表时间：
2006-03-01
影响因子：
2.3
通讯作者：
Kobayashi, Motomasa
中科院分区：
文献类型：
--
作者：
Aoki, Shunji;Cho, Seok-hwan;Kobayashi, Motomasa
从海绵中分离得到Bastadin 6，一个溴化酪氨酸衍生物的大环四聚体，并对其抗血管生成活性进行了评价。与正常成纤维细胞(3Y1)或几种肿瘤细胞(KB3-1、K562和Neuro2A)相比，Bastadin 6对依赖血管内皮生长因子或碱性成纤维细胞生长因子的人脐静脉内皮细胞(HUVECs)的增殖(IC_(50)=0.052µmol/L)有选择性地抑制20~100倍。Bastadin 6还抑制血管内皮生长因子或碱性成纤维细胞生长因子诱导的血管内皮细胞小管形成(0.1mU/L，6h)和血管内皮细胞生长因子诱导的迁移(1mU/L，4h)。此外，Bastadin 6几乎完全阻断了血管内皮生长因子或碱性成纤维细胞生长因子诱导的小鼠角膜新生血管形成，并抑制了S.C.的生长。裸鼠接种A431实体瘤(100 mg/kg)。Bastadin 6诱导HUVECs死亡，呈凋亡表型，但对血管内皮生长因子诱导的血管内皮生长因子受体Fit-1和KDR/Fik-1自身磷酸化无影响。提示BASTADIN 6的抗血管生成作用与选择性诱导血管内皮细胞凋亡密切相关。
Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, was isolated from a marine sponge and its anti-angiogenic activity was evaluated. Bastadin 6 was found to inhibit vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-dependent proliferation (IC50=0.052 mu mol/l) of human umbilical vein endothelial cells (HUVECs) 20- to 100-fold selectively in comparison with normal fibroblast (3Y1) or several tumor cells (KB3-1, K562 and Neuro2A). Bastadin 6 also inhibited VEGF- or bFGF-induced tubular formation (0.1 mu mol/l, 6 h treatment) and VEGF-induced migration (1 mu mol/l, 4h treatment) of HUVECs. Moreover, bastadin 6 almost completely blocked VEGF- or bFGF-induced in vivo neovascularization in the mice corneal assay and suppressed growth of s.c. inoculated A431 solid tumor in nude mice (100 mg/kg, i.p.). Bastadin 6 induced cell death of HUVECs with an apoptotic phenotype, whereas it showed no effect on the VEGF-induced auto-phosphorylation of VEGF receptors FIt-1 and KDR/FIk-1. These results suggest that the anti-angiogenic effect of bastadin 6 is closely related to selective induction activity of apoptosis against endothelial cells.