Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents
Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents
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DOI：
10.1016/s0020-7519(00)00043-6
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发表时间：
2000-05-01
影响因子：
4
通讯作者：
Parsons, PG
中科院分区：
文献类型：
--
作者：
Andrews, KT;Walduck, A;Parsons, PG
恶性疟原虫的组蛋白是抗疟疾药物潜在的新靶点。一种自然产生的化合物apicidin，最近被证明能抑制恶性疟原虫的体外生长。Apicidin可以高乙酰化组蛋白，提示其作用方式是通过抑制组蛋白脱乙酰酶来实现的。我们测试了已知的组蛋白脱乙酰酶抑制剂、哺乳动物肿瘤抑制化合物和细胞分化剂抑制恶性疟原虫药物敏感和耐药株的体外生长的能力。其中7个化合物的MIC50值为MUMIC50值，组蛋白去乙酰化抑制剂和细胞分化剂曲古抑素A在低浓度下具有活性。一种名为琥珀酸二甲基酰胺的化合物，与正常哺乳动物细胞相反，它选择性地抑制肿瘤细胞，在体内对急性小鼠疟疾伯氏疟原虫有细胞抑制作用，该化合物的一轮治疗未能筛选出耐药突变。这些结果表明，组蛋白脱乙酰酶抑制剂和细胞分化剂作为抗疟疾候选药物具有良好的应用前景。(C)2000澳大利亚寄生虫学协会。爱思唯尔科学有限公司出版。保留所有权利。
The histones of Plasmodium falciparum represent a potential new target for anti-malarial compounds. A naturally occurring compound, apicidin, has recently been shown to inhibit the in vitro growth of P. falciparum. Apicidin was shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. We have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitro growth of a drug sensitive and resistant strain of P, falciparum. Seven of the tested compounds had mu M IC50 values, and trichostatin A, a histone deacetylation inhibitor and cytodifferentiating agent, was active at low nM concentrations. One compound, suberic acid bisdimethylamide, which selectively arrests tumour cells as opposed to normal mammalian cells, had an in vivo cytostatic effect against the acute murine malaria Plasmodium berghei, and one round of treatment with the compound failed to select for resistant mutations. These results suggest a promising role for histone deacetylase inhibitors and cytodifferentiating agents as antimalarial drug candidates. (C) 2000 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved.