Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration.
Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration.
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DOI：
10.1021/jm401002r
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发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Liu HM
中科院分区：
文献类型：
--
作者：
Zheng YC;Duan YC;Ma JL;Xu RM;Zi X;Lv WL;Wang MM;Ye XW;Zhu S;Mobley D;Zhu YY;Wang JW;Li JF;Wang ZR;Zhao W;Liu HM
赖氨酸特异性去甲基化酶1（LSD 1）是第一个被发现的组蛋白去甲基化酶，在基因激活和阻遏的表观遗传调控中起重要作用。LSD 1在多种恶性肿瘤中表达上调。本研究设计并合成了五个系列的1，2，3-三唑-二硫代氨基甲酸酯杂合物，并筛选了它们对LSD 1的抑制活性。我们发现这些化合物中的一些，尤其是化合物26，表现出对LSD 1的最特异和最强的抑制。有趣的是，与2-PCPA相比，化合物26还显示出对LSD 1过表达的胃癌细胞系MGC-803和HGC-27的有效和选择性细胞毒性，以及对细胞迁移和侵袭的显著抑制。此外，化合物26在体内有效地减少了人胃癌细胞暴露的肿瘤生长，没有不良副作用的迹象。这些发现表明，化合物26值得进一步研究作为治疗LSD 1过表达胃癌的先导化合物。
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1, 2, 3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.
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