title: Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A.
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.
authors.affiliation: Institute of Physiology, University of Zürich, Zurich, Switzerland.
authors.forename: Pietro E
authors.initials: PE
authors.lastname: Cippà
authors.forename: Jivko
authors.initials: J
authors.lastname: Kamarashev
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kraus
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Laurence
authors.initials: L
authors.lastname: Feldmeyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D006200:Hair Color / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008544:Melanocytes / Q000187:drug effects; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D065095:Calcineurin Inhibitors; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016572:Cyclosporine