HDAC-Bax Multiple Ligands Enhance Bax-Dependent Apoptosis in HeLa Cells.
HDAC-Bax Multiple Ligands Enhance Bax-Dependent Apoptosis in HeLa Cells.
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DOI：
10.1021/acs.jmedchem.0c01454
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发表时间：
2020-10
影响因子：
7.3
通讯作者：
T. Liang;Yi Zhou;Reham M. Elhassan;Xuben Hou;Xinying Yang;H. Fang
中科院分区：
文献类型：
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作者：
T. Liang;Yi Zhou;Reham M. Elhassan;Xuben Hou;Xinying Yang;H. Fang
受Bax激活剂BTSA 1和组蛋白去乙酰化酶（HDAC）抑制剂SAHA协同抑制HeLa细胞生长的启发，合理设计了一系列HDAC-Bax复合配体。化合物23具有与SAHA相似的HDAC抑制活性和与BTSA 1相当的Bax亲和力，其对HeLa细胞表现出上级生长抑制，并且其抗增殖活性分别比BTSA 1和SAHA高15倍和3倍。化合物23具有较好的抗增殖活性和较低的细胞毒性，表明我们的HDAC-Bax多配体设计策略取得了成功。进一步的研究表明，化合物23可以通过上调Bax，随后诱导Bax的构象激活来增强Bax依赖性凋亡。据我们所知，我们首次报道了HDAC-Bax多配体，并证明了一种新的模式，通过增强细胞凋亡依赖性细胞凋亡的实体瘤的治疗。
Inspired by the synergistic effect of BTSA1 (a Bax activator) and SAHA (a histone deacetylase (HDAC) inhibitor) in HeLa cell growth suppression, a series of novel HDAC-Bax multiple ligands were designed rationally. Compound 23, which possesses similar HDAC inhibitory activity relative to SAHA and Bax affinity comparable to BTSA1, exhibits a superior growth suppression against HeLa cells, and its antiproliferative activities are 15-fold and 3-fold higher than BTSA1 and SAHA, respectively. The better antiproliferative activity and lower cytotoxicity of compound 23 indicated that our HDAC-Bax multiple ligand design strategy achieved success. Further studies suggested that compound 23 could enhance Bax-dependent apoptosis by upregulating Bax, followed by inducing the conformational activation of Bax. To our knowledge, we first report HDAC-Bax multiple ligands and demonstrate a new paradigm for the treatment of solid tumors by enhancing Bax-dependent apoptosis.