Dantas A P, Barbosa H S, De Castro S L
Laboratory of Cellular Biology, Department of Cellular Ultrastructure and Biology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil.
J Submicrosc Cytol Pathol. 2003 Jul;35(3):287-94.
Microtubules play fundamental roles in eukaryotic cells and have been investigated as target for drugs. Several studies showed the potential use of anti-microtubule agents against pathogenic protozoa. Taxol has been intensively studied in Leishmania spp. and microtubules have been considered as a promising antileishmanial drug target. It has been also shown that taxol interferes with the proliferation of Trypanosoma cruzi, leading to morphological alterations and interruption of nuclear division and cytokinesis. In the present work we show that T. cruzi bloodstream trypomastigotes were much more susceptible than epimastigotes, and in both forms taxol caused severe ultrastructural damage, especially associated to changes in the shape of the parasites. In trypomastigotes, different degrees of body contortion along the longitudinal axis and a marked dilatation of the flagellar pocket were detected. Treated epimastigotes presented a decrease in the electron density of the mitochondrial matrix, absence of mitochondrial cristae and an increase in the number of lipid droplets. Bizarre multi-flagellar epimastigotes were also detected, suggesting an interruption of the cytokinesis. Taxol caused no noticeable ultrastructural alterations on sub-pellicular and flagellar microtubules of both evolutive forms of T. cruzi. As already described in the literature, such structures in trypanosomatids are very resistant to microtubule disrupters when compared to those in mammalian cells. Taxol prevented the endocytosis of albumin-gold complexes by epimastigotes, and this result could be associated to the loss of the dynamic stability of the microtubules of the cytostome.
微管在真核细胞中发挥着重要作用，并且已被作为药物作用靶点进行研究。多项研究表明抗微管药物对致病性原生动物具有潜在用途。紫杉醇已在利什曼原虫属中得到深入研究，微管被认为是一种有前景的抗利什曼原虫药物靶点。研究还表明，紫杉醇会干扰克氏锥虫的增殖，导致形态改变以及核分裂和胞质分裂中断。在本研究中，我们发现克氏锥虫血液内型锥鞭毛体比无鞭毛体更易受影响，并且在这两种形态中，紫杉醇都会造成严重的超微结构损伤，尤其是与寄生虫形状变化相关的损伤。在锥鞭毛体中，检测到沿纵轴不同程度的身体扭曲以及鞭毛袋明显扩张。经处理的无鞭毛体线粒体基质电子密度降低，线粒体嵴消失，脂滴数量增加。还检测到怪异的多鞭毛无鞭毛体，这表明胞质分裂中断。紫杉醇对克氏锥虫两种进化形态的表膜下微管和鞭毛微管均未造成明显的超微结构改变。正如文献中已描述的那样，与哺乳动物细胞中的微管相比，锥虫类生物中的此类结构对微管破坏剂具有很强的抗性。紫杉醇阻止了无鞭毛体对白蛋白 - 金复合物的内吞作用，这一结果可能与胞口微管动态稳定性的丧失有关。
