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

Cippà, Pietro ; Kamarashev, Jivko ; Chen, Jin ; Kraus, Anna ; Segerer, Stephan ; Feldmeyer, Laurence ; Fehr, Thomas

In: Apoptosis, 2013, vol. 18, no. 3, p. 315-323

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    Title
    • Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A
    Author
    • Cippà, Pietro. Institute of Physiology, University of Zürich, Zurich, Switzerland
    • Kamarashev, Jivko. Department of Dermatology, University Hospital, Zurich, Switzerland
    • Chen, Jin. Institute of Physiology, University of Zürich, Zurich, Switzerland
    • Kraus, Anna. Institute of Physiology, University of Zürich, Zurich, Switzerland
    • Segerer, Stephan. Division of Nephrology, University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland
    • Feldmeyer, Laurence. Department of Dermatology, University Hospital, Zurich, Switzerland
    • Fehr, Thomas. Institute of Physiology, University of Zürich, Zurich, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:316368
    Summary
    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