Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex

Nilkantha Sen, B. Banerjee, B. B. Das, A. Ganguly, T. Sen, S. Pramanik, S. Mukhopadhyay, H. K. Majumder

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of ΔΨm and generates ROS inside cells. Loss of ΔΨm leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.

Original languageEnglish (US)
Pages (from-to)358-367
Number of pages10
JournalCell Death and Differentiation
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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