Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth.
Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth.
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DOI：
10.1016/j.ijpddr.2016.12.005
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发表时间：
2017-04
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：
Chua MJ;Arnold MS;Xu W;Lancelot J;Lamotte S;Späth GF;Prina E;Pierce RJ;Fairlie DP;Skinner-Adams TS;Andrews KT
疟疾、血吸虫病和利什曼病是最流行的热带寄生虫病，每种疾病都需要新的创新治疗方法。针对寄生虫的基本途径，如调节基因表达和细胞周期进程的途径，是发现新药先导的关键策略。在本研究中，检测了靶向组蛋白/赖氨酸脱乙酰酶的四种临床批准的抗癌药物（伏立诺他、贝利诺他、帕比司他和罗米地辛）对诺氏疟原虫、曼氏血吸虫、亚马逊利什曼原虫和杜氏利什曼原虫寄生虫的体外活性，以及两种在小鼠疟疾模型中的体内活性。所有四种化合物都是诺氏疟原虫疟疾寄生虫的有效抑制剂（IC 50 9-370 nM），贝利司他、帕比司他和伏立诺他对寄生虫的选择性是人新生儿包皮成纤维细胞（NFF）或人胚肾（HEK 293）细胞的8-45倍，而罗米地辛没有选择性。每种HDAC抑制剂药物引起诺氏毕赤酵母组蛋白H4的超乙酰化。所有药物均对利什曼原虫无鞭毛体或前鞭毛体寄生虫（IC 50> 20 μM）或曼氏血吸虫童虫（IC 50> 10 μM）无活性，但罗米地辛抑制曼氏血吸虫成虫产卵和产卵（IC 50> 10 μM）。在口服给予伏立诺他或帕比司他（25 mg/kg，每天两次，持续4天）的伯氏疟原虫感染的小鼠中观察到适度的体内活性，分别在感染后第4-7天和第4-10天观察到寄生虫血症的显著减少（P < 0.05）。HDAC抑制剂癌症药物具有针对诺氏疟原虫的体外活性。HDAC抑制剂药物引起诺氏疟原虫组蛋白H4的超乙酰化。HDAC抑制剂药物对利什曼原虫无鞭毛体或前鞭毛体没有活性。罗米地辛抑制曼氏血吸虫成虫的剥落和产卵。口服帕比司他在伯氏疟原虫感染的小鼠中具有比伏立诺他更好的活性。
Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM), with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P < 0.05), respectively. HDAC inhibitor cancer drugs have in vitro activity against P. knowlesi. HDAC inhibitor drugs cause hyperacetylation of P. knowlesi histone H4. HDAC inhibitor drugs are not active against Leishmania amastigotes or promastigotes. Romidepsin inhibited S. mansoni adult worm parings and egg production. Oral Panobinostat has better activity in P. berghei infected mice than Vorinostat.