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

作者：Sen N; Banerjee B; Das B B; Ganguly A; Sen T; Pramanik S; Mukhopadhyay S; Majumder H K^*

来源：Cell Death and Differentiation, 2007, 14(2): 358-367.

DOI：10.1038/sj.cdd.4402002

• protein kinase
• Withaferin A
• staurosporine
• DNA topoisomerase I
• apoptosis
• Leishmania donovani

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 Delta Psi(m) and generates ROS inside cells. Loss of Delta Psi(m) 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.

• 出版日期2007-2