Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites.
Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites.
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DOI：
10.1016/j.ijpddr.2015.05.004
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Andrews KT
中科院分区：
文献类型：
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作者：
Engel JA;Jones AJ;Avery VM;Sumanadasa SD;Ng SS;Fairlie DP;Skinner-Adams T;Andrews KT
组蛋白脱乙酰基酶（HDAC）与组蛋白乙酰基转移酶（HAT）一起工作以可逆地乙酰化组蛋白和非组蛋白蛋白。因此，这些酶参与调节染色质结构和基因表达以及其他重要的细胞过程。HDAC是某些类型癌症的经验证的药物靶点，有四种HDAC抑制剂在临床上获得批准。然而，它们也显示出作为其他适应症（包括疟疾和其他寄生虫病）的新药物靶点的前景。在这项研究中，对四种抗癌HDAC抑制剂针对引起疟疾和锥虫病的寄生虫的体外活性进行了检查。这些抑制剂中的三种，辛二酰苯胺异羟肟酸（SAHA; vorinostat®）、罗米地辛（Istodax®）和贝利司他（Beleodaq®），在临床上被批准用于治疗T细胞淋巴瘤，而第四种，帕比司他，最近已被批准用于某些多发性骨髓瘤患者的联合治疗。发现所有HDAC抑制剂均在纳摩尔范围内（IC 50 10-200 nM）抑制无性期恶性疟原虫疟疾寄生虫的生长，而只有罗米地辛在亚μM浓度下对血流形式的布氏锥虫有活性（IC 50 35 nM）。发现这些化合物与哺乳动物细胞相比对疟疾寄生虫具有一定的选择性，但与哺乳动物细胞相比对锥虫寄生虫没有选择性。所有化合物引起恶性疟原虫无性阶段寄生虫中的组蛋白和非组蛋白的超乙酰化，并且除了重组PfHDAC 1活性之外，还抑制恶性疟原虫核提取物中的脱乙酰酶活性。恶性疟原虫组蛋白超乙酰化数据表明，HDAC抑制剂可能差异影响组蛋白H3和H4的乙酰化概况。四种临床批准的抗癌HDAC抑制剂有效抑制恶性疟原虫。只有罗米地辛对T. B有活性。布鲁氏菌寄生虫所有化合物均为恶性疟原虫中的高乙酰化组蛋白和非组蛋白。疟原虫组蛋白乙酰化的一些差异的影响进行了观察。所有化合物抑制疟原虫核脱乙酰酶活性和PfHDAC 1。
Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat®), romidepsin (Istodax®) and belinostat (Beleodaq®), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10–200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4. Four clinically approved anti-cancer HDAC inhibitors potently inhibited P. falciparum. Only one, Romidepsin, was active against T. b. brucei parasites. All compounds hyperacetylated histone and non-histone proteins in P. falciparum. Some differential effects on Plasmodium histone acetylation were observed. All compounds inhibited Plasmodium nuclear deacetylase activity and PfHDAC1.