Camptothecin induced mitochondrial dysfunction\ud leading to programmed cell death in unicellular\ud hemoflagellate Leishmania donovani

摘要

The parasites of the order kinetoplastidae including Leishmania\udspp. emerge from most ancient phylogenic branches of\udunicellular eukaryotic lineages. In their life cycle, topoisomerase\udI plays a significant role in carrying out vital cellular\udprocesses. Camptothecin (CPT), an inhibitor of DNA topoisomerase\udI, induces programmed cell death (PCD) both in the\udamastigotes and promastigotes form of L. donovani parasites.\udCPT-induced cellular dysfunction in L. donovani promastigotes\udis characterized by several cytoplasmic and nuclear\udfeatures of apoptosis. CPT inhibits cellular respiration that\udresults in mitochondrial hyperpolarization taking place by\udoligomycin-sensitive F0-F1 ATPase-like protein in leishmanial\udcells. During the early phase of activation, there is an increase\udin reactive oxygen species (ROS) inside cells, which causes\udsubsequent elevation in the level of lipid peroxidation and\uddecrease in reducing equivalents like GSH. Endogenous ROS\udformation and lipid peroxidation cause eventual loss of\udmitochondrial membrane potential. Furthermore, cytochrome\udc is released into the cytosol in a manner independent of\udinvolvement of CED3/CPP32 group of proteases and unlike\udmammalian cells it is insensitive to cyclosporin A. These\udevents are followed by activation of both CED3/CPP32 and\udICE group of proteases in PCD of Leishmania. Taken together,\udour study indicates that different biochemical events leading\udto apoptosis in leishmanial cells provide information that could\udbe exploited to develop newer potential therapeutic targets.\udCell Death and Differentiation (2004) 11, 924–936.