Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS.
Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS.
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发现(4-溴苯基)(3-羟基-4-甲氧基苯基)甲酮通过上调hTERT诱导细胞凋亡和ERS
DOI：
10.1038/cddis.2017.384
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发表时间：
2017-08-24
影响因子：
9
通讯作者：
Liu XH
中科院分区：
文献类型：
--
作者：
Cheng X;Shi JB;Liu H;Chen LZ;Wang Y;Tang WJ;Liu XH
端粒酶hTERT的显性负突变体被证明在肿瘤细胞中具有选择性作用。然而，迄今为止还没有开发出任何有效的和高选择性的hTERT抑制剂。我们致力于开发新的hTERT调节剂，并合成了一种小分子化合物，命名为（4-溴苯基）（3-羟基-4-甲氧基苯基）甲酮。体外研究发现，标题化合物对端粒酶有较强的抑制活性，对SMMC-7721细胞有较强的抑制增殖作用，其IC 50值为88 nm，对人正常肝细胞无明显毒性作用，其IC 50值为10 μM。我们的体内研究表明，该化合物在异种移植肿瘤模型中显著抑制肿瘤生长。进一步探讨标题化合物通过调节hTERT抑制SMMC-7721细胞增殖的分子机制;结果表明，内质网应激（ERS）通过ER过度反应（EOR）激活hTERT的表达，然后诱导ERS，其被认为与氧化应激和线粒体功能障碍复杂相关，导致凋亡性细胞死亡，从而调节下游信号分子的表达，包括CHOP（CAAT/增强子结合蛋白同源蛋白））和凋亡途径，导致细胞增殖的抑制。
Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC50 value 10 μM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation.
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