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

N. Sen, B. B. Das, A. Ganguly, T. Mukherjee, G. Tripathi, S. Bandyopadhyay, S. Rakshit, T. Sen, H. K. Majumder

Research output: Contribution to journalArticle

178 Scopus citations

Abstract

The parasites of the order kinetoplastidae including Leishmania spp. emerge from most ancient phylogenic branches of unicellular eukaryotic lineages. In their life cycle, topoisomerase I plays a significant role in carrying out vital cellular processes. Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces programmed cell death (PCD) both in the amastigotes and promastigotes form of L. donovani parasites. CPT-induced cellular dysfunction in L. donovani promastigotes is characterized by several cytoplasmic and nuclear features of apoptosis. CPT inhibits cellular respiration that results in mitochondrial hyperpolarization taking place by oligomycin-sensitive F0-F1 ATPase-like protein in leishmanial cells. During the early phase of activation, there is an increase in reactive oxygen species (ROS) inside cells, which causes subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents like GSH. Endogenous ROS formation and lipid peroxidation cause eventual loss of mitochondrial membrane potential. Furthermore, cytochrome c is released into the cytosol in a manner independent of involvement of CED3/CPP32 group of proteases and unlike mammalian cells it is insensitive to cyclosporin A. These events are followed by activation of both CED3/CPP32 and ICE group of proteases in PCD of Leishmania. Taken together, our study indicates that different biochemical events leading to apoptosis in leishmanial cells provide information that could be exploited to develop newer potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)924-936
Number of pages13
JournalCell Death and Differentiation
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2004

Keywords

  • Apoptosis
  • Camptothecin
  • DNA topoisomerase I
  • Leishmania
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Sen, N., Das, B. B., Ganguly, A., Mukherjee, T., Tripathi, G., Bandyopadhyay, S., Rakshit, S., Sen, T., & Majumder, H. K. (2004). Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani. Cell Death and Differentiation, 11(8), 924-936. https://doi.org/10.1038/sj.cdd.4401435