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Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

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Abstract

Survival of lymphocytes and melanocyte stem cells critically depends on B cell lymphoma 2 (Bcl-2). In T lymphocytes, a basal calcineurin activity maintains Bcl-2 expression in naïve cells, and the activation of the calcineurin pathway orchestrates the regulation of the intrinsic apoptosis pathway after antigen recognition. Therefore, calcineurin inhibitors might potentiate the pro-apoptotic effect of pharmacological Bcl-2 inhibitors on lymphatic cells. In vitro, a reduced Bcl-2 expression in lymphocytes exposed to calcineurin inhibitors increased their sensitivity to the small molecule Bcl-2 inhibitor ABT-737. This correlated with an augmented pro-apoptotic activity of ABT-737 on lymphocytes in combination with cyclosporine A in naïve mice in vivo. Interestingly, similar processes were observed in melanocytes. ABT-737 induced a fur depigmentation at the site of injection, and this effect was expanded to a generalized depigmentation in combination with cyclosporine A. Thus, inhibiting calcineurin increases the pro-apoptotic potency of ABT-737 in cells depending on Bcl-2 for survival. The increased efficacy of Bcl-2 inhibitors in combination with cyclosporine A might be relevant to exploit their anti-neoplastic and immuno-modulatory properties.

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Acknowledgments

We thank Philip D Bardwell and Abbott (Worcester, USA) for providing ABT-737, Andreas Strasser and Martin Hausmann for the Bim−/− mouse, and K. Bruni and her team for the blood analyses. The project was supported by the Swiss National Science Foundation (Grant No. 323530–133893 to PEC, 310000–121979 to TF, 32003B_129710 to SS) and the Olga Mayenfisch Stiftung.

Conflict of interest

We do not have any conflict of interest to declare.

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Authors and Affiliations

  1. Institute of Physiology, University of Zürich, Zurich, Switzerland

    Pietro E. Cippà, Jin Chen, Anna K. Kraus & Thomas Fehr

  2. Division of Nephrology, University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland

    Pietro E. Cippà, Jin Chen, Anna K. Kraus, Stephan Segerer & Thomas Fehr

  3. Department of Dermatology, University Hospital, Zurich, Switzerland

    Jivko Kamarashev & Laurence Feldmeyer

  4. Department of Anatomy, University of Zürich, Zurich, Switzerland

    Stephan Segerer

Authors
  1. Pietro E. Cippà
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  2. Jivko Kamarashev
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  3. Jin Chen
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  4. Anna K. Kraus
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  7. Thomas Fehr
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Corresponding author

Correspondence to Thomas Fehr.

Additional information

Laurence Feldmeyer and Thomas Fehr contributed equally to this work.

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Cippà, P.E., Kamarashev, J., Chen, J. et al. Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A. Apoptosis 18, 315–323 (2013). https://doi.org/10.1007/s10495-012-0778-2

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  • DOI: https://doi.org/10.1007/s10495-012-0778-2

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