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Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1

Leukemia volume 17, pages 1981–1989 (2003)Cite this article

Abstract

New agents are required for the treatment of chronic lymphocytic leukaemia (CLL). We show here that a protein kinase C inhibitor, bisindolylmaleimide IX, is a potent inducer of apoptosis in CLL cells, and investigate the mechanisms by which this is induced. Bisindolylmaleimide IX induced a conformational change and subcellular redistribution of Bax from the cytosol to the mitochondria, resulting in the release of the proapoptotic mediators cytochrome c, Smac and Omi/HtrA2 from the mitochondrial inner membrane space. This was followed by the activation of caspase-9 as the apical caspase and subsequent activation of effector caspases. CLL cells undergoing apoptosis showed a rapid caspase-mediated cleavage of Mcl-1, an antiapoptotic member of the Bcl-2 family implicated in CLL survival and poor prognosis. This cleavage was mediated primarily by caspase-3. Cleavage of Mcl-1 may provide a feed-forward amplification loop, resulting in the rapid induction of apoptosis. Bisindolylmaleimide IX or a related derivative may be of clinical use in the treatment of CLL.

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Acknowledgements

We thank Dr Dave Dinsdale for the electron microscopy studies, Dr G Packham for the cDNA for Mcl-1 and Dr Emad Alnemri for the Omi construct. This work was supported in part by the Medical Research Council and a grant from the European Union (Grant # QLG1-1999-00739).

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  1. MRC Toxicology Unit, University of Leicester, Leicester, UK

    R T Snowden, X-M Sun, M J S Dyer & G M Cohen

  2. Department of Hematology, University of Leicester, Leicester, UK

    M J S Dyer

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Snowden, R., Sun, XM., Dyer, M. et al. Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1. Leukemia 17, 1981–1989 (2003). https://doi.org/10.1038/sj.leu.2403088

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