Discovery of polyoxometalate-based HDAC inhibitors with profound anticancer activity in vitro and in vivo
Discovery of polyoxometalate-based HDAC inhibitors with profound anticancer activity in vitro and in vivo
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发现基于多金属氧酸盐的 HDAC 抑制剂，在体外和体内具有深远的抗癌活性
DOI：
10.1016/j.ejmech.2011.03.036
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发表时间：
2011-06-01
影响因子：
6.7
通讯作者：
Liu, Shuxia
中科院分区：
文献类型：
--
作者：
Dong, Zhixiong;Tan, Ruikang;Liu, Shuxia
我们利用以p21基因启动子为靶点的细胞筛选系统，从聚氧乙烯酸（POM）文库中获得了5个阳性的新型组蛋白去乙酰化酶抑制剂（HDACIs）。其中，PAC-320，一种新的三有机锡取代的锗钨酸盐，显示出显着的细胞外抑制活性。同时，用X射线晶体学对PAC-320的晶体结构进行了表征。紫外光谱、循环伏安和热重分析表明，PAC-320在生理条件下能稳定存在。PAC-320对细胞内HDAC活性具有较强的抑制作用。更重要的是，PAC-320抑制多种癌细胞的生长，并且在肝癌H22细胞小鼠模型中显示出显著的抗癌效果。这项研究首次揭示了HDAC抑制活性是POM发挥其抗癌作用的机制。(C)2011年Elsevier Masson SAS。All rights reserved.
We obtained 5 positive novel histone deacetylase inhibitors (HDACIs) from a polyoxometalate (POM) library by using a cell-based screening system targeting the p21 gene promoter. Among them, PAC-320, a new tri-organic-tin-substitute germanotungstate, displayed remarkable extracellular inhibitory activity. Meanwhile, the crystal structure of PAC-320 was characterized by X-ray crystallography. PAC-320 could stably exist under physiological conditions as revealed by UV spectrum, CV and TG. PAC-320 possessed a strong inhibitory effect to intracellular HDAC activity. More significantly, PAC-320 inhibited the growth of a variety of cancer cells, and exhibited remarkable anticancer effect in a hepatocarcinoma H22 cell mice model. This study revealed, for the first time, that the HDAC inhibitory activity is a mechanism by which POMs exert their anticancer effect. (C) 2011 Elsevier Masson SAS. All rights reserved.