Vannier-Santos M A, Urbina J A, Martiny A, Neves A, de Souza W
Programa de Parasitologia e Biologia Celular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil.
J Eukaryot Microbiol. 1995 Jul-Aug;42(4):337-46. doi: 10.1111/j.1550-7408.1995.tb01591.x.
The antiproliferative effects and ultrastructural alterations induced in vitro by two antifungal compounds, the azole ketoconazole and the allylamine terbinafine on Leishmania amazonensis are reported. Promastigotes treatment with ketoconazole and terbinafine induced growth arrest and cell lysis in 72 hours. Combination of the two agents produced additive effects on promastigote axenic growth and synergistic effects on intracellular amastigote proliferation. The amastigotes, either axenically grown or infecting murine macrophages, were about 100-fold more sensitive to the drugs. These compounds induced the appearance of large multivesicular bodies, especially after ketoconazole treatment, increased amount of lipid inclusions as well as numerous, polymorphic volutin granules, particularly in terbinafine-treated cells. Multivesicular bodies were observed in close apposition with organelles such as mitochondria, which also showed alterations in the distribution and appearance of cristae, and the formation of paracrystalline arrays within the matrix. Some cells presented large portions of cytoplasm wrapped by endoplasmic reticulum and many parasites also presented myelin-like endoplasmic reticulum profiles. Such alterations together with the strong acid phosphatase activity observed in the multivesicular bodies and volutin granules may indicate the existence of an unusual autophagic process in cells treated with ergosterol biosynthesis inhibitors.
报道了两种抗真菌化合物——唑类酮康唑和烯丙胺类特比萘芬在体外对亚马逊利什曼原虫诱导的抗增殖作用和超微结构改变。用酮康唑和特比萘芬处理前鞭毛体，在72小时内诱导生长停滞和细胞裂解。两种药物联合使用对前鞭毛体体外生长产生相加作用，对细胞内无鞭毛体增殖产生协同作用。无鞭毛体，无论是体外培养还是感染小鼠巨噬细胞，对这些药物的敏感性都高约100倍。这些化合物诱导出现大量多囊泡体，尤其是在酮康唑处理后，脂质包涵体数量增加，以及大量多形性异染粒，特别是在特比萘芬处理的细胞中。观察到多囊泡体与线粒体等细胞器紧密相邻，线粒体的嵴在分布和外观上也出现改变，基质内形成副晶状排列。一些细胞呈现出被内质网包裹的大部分细胞质，许多寄生虫也呈现出髓鞘样内质网形态。这些改变以及在多囊泡体和异染粒中观察到的强酸性磷酸酶活性，可能表明在用麦角固醇生物合成抑制剂处理的细胞中存在异常的自噬过程。
