Inhibition of tubulin polymerization by vitilevuamide, a bicyclic marine peptide, at a site distinct from colchicine, the vinca alkaloids, and dolastatin 10
Inhibition of tubulin polymerization by vitilevuamide, a bicyclic marine peptide, at a site distinct from colchicine, the vinca alkaloids, and dolastatin 10
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DOI：
10.1016/s0006-2952(01)00898-x
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发表时间：
2002-02-15
影响因子：
5.8
通讯作者：
Barrows, LR
中科院分区：
文献类型：
--
作者：
Edler, MC;Fernandez, AM;Barrows, LR
Vitilevuamide，双环13氨基酸肽。从两种海鞘Didemnum cuculiferum和Polysyncranton lithostrotum中分离得到。Vitilevuamide在几种人肿瘤细胞系中具有细胞毒性，LC 50值范围为6至311 nM，在25细胞系面板中的分析显示与几种紫杉醇类似物的弱相关性。Vitilevuamide是强阳性的微管蛋白聚合抑制剂的细胞为基础的屏幕。9 μ g/mL（5.6 μ M）的Vitilevuamide具有与25 μ g/mL（62.5 μ M）的秋水仙碱的最大效果相当的效果。Vitilevuamide在体内对P388淋巴细胞性白血病有活性，在30 μ g/kg剂量下可使白血病小鼠的寿命延长70%。我们推测，至少部分的vitilevuamide的细胞毒性机制是由于其抑制微管蛋白聚合。发现Vitilevuamide在体外抑制纯化的微管蛋白的聚合，其IC 50值约为2 μ M。细胞周期分析显示，葡萄糖醛酸酰胺将细胞阻滞在G（2）/M期，16小时后78%的处理细胞为四倍体。Vitilevuamide表现出非竞争性抑制长春碱结合微管蛋白。秋水仙碱结合微管蛋白的稳定在vitilevuamide的存在下，以类似于长春碱的方式。多拉司他丁10结合在低浓度下不受vitilevuamide的影响，但在较高浓度下受到抑制。还发现谷丙酰胺的存在对GTP结合的影响很弱。这些结果表明，vitilevuamide通过在一个独特的网站相互作用抑制微管蛋白聚合的可能性。(C)2002年由Elsevier Science Inc.出版
Vitilevuamide, a bicyclic 13 amino acid peptide. was isolated from two marine ascidians, Didemnum cuculiferum and Polysyncranton lithostrotum. Vitilevuamide was cytotoxic in several human tumor cell lines, with LC50 values ranging from 6 to 311 nM, and analysis in a 25-cell line panel revealed a weak correlation with several taxol analogs. Vitilevuamide was strongly positive in a cell-based screen for inhibitors of tubulin polymerization. Vitilevuamide at 9 mug/mL (5.6 muM) had an effect equivalent to the maximal effect of colchicine at 25 mug/mL (62.5 muM). Vitilevuamide was active in vivo against P388 lymphocytic leukemia, increasing the lifespan of leukemic mice 70% at 30 mug/kg. We hypothesized that at least part of the cytotoxic mechanism of vitilevuamide was due to its inhibition of tubulin polymerization. Vitilevuamide was found to inhibit polymerization of purified tubulin in vitro, with an IC50 value of approximately 2 muM. Cell cycle analysis showed that vitilevuamide arrested cells in the G(2)/M phase with 78% of treated cells tetraploid after 16 hr. Therefore, vitilevuamide was tested for its ability to inhibit binding of known tubulin ligands. Vitilevuamide exhibited non-competitive inhibition of vinblastine binding to tubulin. Colchicine binding to tubulin was stabilized in the presence of vitilevuamide in a fashion similar to vinblastine. Dolastatin 10 binding was unaffected by vitilevuamide at low concentrations, but inhibited at higher ones. GTP binding was also found to be weakly affected by the presence of vitilevuamide. These results suggest the possibility that vitilevuamide inhibits tubulin polymerization via an interaction at a unique site. (C) 2002 Published by Elsevier Science Inc.