Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
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DOI：
10.1093/emboj/20.24.6969
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发表时间：
2001-12-17
期刊：
影响因子：
11.4
通讯作者：
Heinzel, T
中科院分区：
文献类型：
--
作者：
Göttlicher, M;Minucci, S;Heinzel, T
组蛋白脱乙酰酶(HDACs)在转录调控和肿瘤发病机制中发挥重要作用。因此，HDAC抑制剂是肿瘤分化治疗的候选药物。在这里，我们证明了耐受性良好的抗癫痫药物丙戊酸是一种强大的HDAC抑制剂。丙戊酸解除依赖于HDAC的转录抑制，并在培养细胞和体内引起组蛋白的超乙酰化。丙戊酸在体外抑制HDAC活性，很可能是通过与HDAC的催化中心结合来实现的。最重要的是，丙戊酸可诱导急性髓系白血病患者的癌细胞、转化的造血祖细胞和白血病母细胞分化。此外，在动物实验中，肿瘤的生长和转移形成显著减少。因此，丙戊酸有可能成为治疗癌症的有效药物。
Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. Moreover, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.