Marine bromophenol bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, induces mitochondrial apoptosis in K562 cells and inhibits topoisomerase I in vitro
Marine bromophenol bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, induces mitochondrial apoptosis in K562 cells and inhibits topoisomerase I in vitro
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海洋溴苯酚双(2,3-二溴-4,5-二羟基苯甲基)醚在体外诱导 K562 细胞线粒体凋亡并抑制拓扑异构酶 I。
DOI：
10.1016/j.toxlet.2012.03.771
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发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
Lin, Xiukun
中科院分区：
文献类型：
--
作者：
Liu, Ming;Zhang, Wei;Lin, Xiukun
双（2，3-二溴-4，5-二羟基苄基）醚（BDDE）是一种来源于海藻的海洋溴酚类化合物。先前的报道表明BDDE具有细胞毒活性。然而，其凋亡活性的机制以及其潜在的细胞靶点仍不清楚。本研究表明，BDDE显示出广谱的体外抗癌能力，并通过线粒体途径在K562细胞中显示出强有力的凋亡活性。进一步的研究表明，BDDE抑制拓扑异构酶I的活性，但不刺激拓扑异构酶I-DNA复合物的形成，也不嵌入DNA。溴化乙锭置换荧光分析和分子模拟结果表明，BDDE主要作用于DNA，与DNA小沟结合，从而抑制拓扑异构酶I的活性。本研究的结果表明，BDDE，它具有独特的化学结构不同于目前的拓扑异构酶I抑制剂，可以作为一个铅模板，合理的药物设计和未来的抗癌药物的发展。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a marine bromophenol compound derived from marine algae. Previous reports have shown that BDDE possesses cytotoxic activity. However, the mechanisms of its apoptotic activity as well as its potential cellular targets remain unclear. The present study demonstrated that BDDE displays broad-spectrum in vitro anticancer capabilities and exhibits potent apoptotic activity in K562 cells via mitochondrial pathway. Further study revealed that BDDE inhibits the activity of topoisomerase I but does not stimulate the formation of topoisomerase I-DNA complex nor intercalate into DNA. Ethidium bromide displacement fluorescence assay and molecular modeling results showed that BDDE mainly targets DNA and binds to DNA minor groove, and thereafter inhibits the activity of topoisomerase I. The results of this study indicated that BDDE, which has unique chemical structure different from current topoisomerase I inhibitors, could serve as a lead template for rational drug design and for future anticancer agents development. (C) 2012 Elsevier Ireland Ltd. All rights reserved.