Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?
Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?
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DOI：
10.1016/j.phymed.2014.06.005
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发表时间：
2014-09-25
期刊：
影响因子：
7.9
通讯作者：
Galanti, N.
中科院分区：
文献类型：
--
作者：
Jimenez, V.;Kemmerling, U.;Galanti, N.
背景：查加斯病或美洲锥虫病是由鞭毛原生动物寄生虫克氏锥虫（T。cruzi），被世界卫生组织认定为世界上17种被忽视的热带疾病之一。目前只有两种药物（苯咪唑，Bz和硝呋莫司，Nx）被接受用于治疗，但它们会引起严重的不良反应，其疗效仍有争议。目的：寄生虫的程序性细胞死亡（PCD）提供了有趣的新的治疗靶点。本工作的目的是评估T.材料与方法：从大花海芋（Gaillardia megapotamica）和道格拉斯蒿（Artemisia douglassiana Besser）的地上部分中分离得到两种天然倍半萜内酯类化合物脱氢亮甲素（DhL）和海伦娜灵（Hln）。化合物的纯度（大于95%）通过C-13-核磁共振，熔点分析和旋光度确认。T.通过暴露于寄生虫表面的磷脂酰丝氨酸和使用TUNEL法检测DNA片段化来测定DhL、Hln、Bz和Nx对克氏上鞭毛体和锥鞭毛体的影响。结果：DhL和Hln这两种天然STL均能诱导T.克鲁兹有趣的是，两种传统的抗真菌药物（Bz和Nx）不诱导程序性细胞死亡。DhL与Bz或Nx联合使用，可增强天然化合物和合成药物对疟原虫活力的抑制作用。Cruzi复制性外鞭毛体和感染性锥鞭毛体形式，这是与杀死寄生虫的常规药物不同的作用机制。因此，DhL和Hln可以单独或与常规药物组合为治疗恰加斯病提供有趣的选择。(C)2014爱思唯尔有限公司All rights reserved.
Background: Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new, drugs.Purpose: Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx.Material and Methods: Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by C-13-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method.Results: The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability.Conclusion: DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, alone or in combination with conventional drugs. (C) 2014 Elsevier GmbH. All rights reserved.