Göttlicher M, Minucci S, Zhu P, Krämer O H, Schimpf A, Giavara S, Sleeman J P, Lo Coco F, Nervi C, Pelicci P G, Heinzel T
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, H.-v.-Helmholtz-Platz 1, D-76344 Eggenstein, Germany.
EMBO J. 2001 Dec 17;20(24):6969-78. doi: 10.1093/emboj/20.24.6969.
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. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.
组蛋白去乙酰化酶（HDACs）在转录调控和癌症发病机制中发挥着重要作用。因此，HDAC抑制剂是癌症分化治疗的候选药物。在此，我们表明耐受性良好的抗癫痫药物丙戊酸是一种强大的HDAC抑制剂。丙戊酸可缓解HDAC依赖性转录抑制，并在培养细胞和体内导致组蛋白的超乙酰化。丙戊酸在体外抑制HDAC活性，很可能是通过与HDACs的催化中心结合。最重要的是，丙戊酸可诱导癌细胞、转化的造血祖细胞以及急性髓系白血病患者白血病原始细胞的分化。此外，在动物实验中肿瘤生长和转移形成显著减少。因此，丙戊酸可能作为一种有效的癌症治疗药物。
