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首页> 外文期刊>Biochemical Pharmacology >HMBA depolymerizes microtubules, activates mitotic checkpoints and induces mitotic block in MCF-7 cells by binding at the colchicine site in tubulin.
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HMBA depolymerizes microtubules, activates mitotic checkpoints and induces mitotic block in MCF-7 cells by binding at the colchicine site in tubulin.

机译：HMBA解聚微管，激活有丝分裂检查点，并通过结合微管蛋白中的秋水仙碱位点诱导MCF-7细胞的有丝分裂阻滞。

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摘要

10-[(3-Hydroxy-4-methoxybenzylidene)]-9(10H)-anthracenone (HMBA), a synthetic compound, has been reported to have a potent antitumor activity. In this study, we found that HMBA depolymerized microtubules in MCF-7 cells and produced aberrant spindles in the MCF-7 cells. It also reduced the distance between the centrosomes and activated the mitotic checkpoint proteins BubR1 and Mad2. Further, HMBA inhibited the progression of MCF-7 cells in mitosis and induced apoptotic cell death involving p53 pathway. In vitro, HMBA bound to purified brain tubulin with a dissociation constant of 4.1+/-0.9 microM. It inhibited microtubule assembly and increased the GTP hydrolysis rate of microtubule assembly. The compound did not alter the binding of 2'(or 3')-O-(trinitrophenyl) guanosine 5'-triphosphate (TNP-GTP), a fluorescent analogue of GTP, to tubulin suggesting that it did not inhibit the binding of GTP to tubulin. However, we obtained evidence indicating that HMBA perturbed the conformation of the GTP binding site in tubulin. In addition, an analysis of the modified Dixon plot suggested that HMBA competitively inhibited the binding of colchicine to tubulin. A computational analysis of the binding of HMBA to tubulin supported the finding that HMBA shared its binding site with colchicine in tubulin and indicated that the binding of HMBA to tubulin was primarily stabilized through hydrogen bonding.
机译：据报道，合成化合物10-[（3-羟基-4-甲氧基亚苄基）]-9（10H）-蒽酮（HMBA）具有有效的抗肿瘤活性。在这项研究中，我们发现HMBA在MCF-7细胞中解聚了微管，并在MCF-7细胞中产生了异常的纺锤体。它还缩短了中心体之间的距离，并激活了有丝分裂检查点蛋白BubR1和Mad2。此外，HMBA抑制有丝分裂中MCF-7细胞的进程，并诱导涉及p53途径的凋亡细胞死亡。在体外，HMBA以4.1 +/- 0.9 microM的解离常数结合纯化的脑微管蛋白。它抑制了微管组装，并增加了微管组装的GTP水解速率。该化合物没有改变GTP的荧光类似物2'（或3'）-O-（三硝基苯基）鸟苷5'-三磷酸（TNP-GTP）与微管蛋白的结合，表明它不抑制GTP的结合微管蛋白。但是，我们获得的证据表明HMBA干扰了微管蛋白中GTP结合位点的构象。此外，对修改后的狄克逊图的分析表明，HMBA竞争性抑制秋水仙碱与微管蛋白的结合。对HMBA与微管蛋白结合的计算分析支持了以下发现：HMBA与微管蛋白中的秋水仙碱共享其结合位点，并表明HMBA与微管蛋白的结合主要通过氢键稳定。

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