title: BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation.
abstract: Apoptosis in megakaryocytes results in the formation of platelets. The role of apoptotic pathways in platelet turnover and in the apoptotic-like changes seen after platelet activation is poorly understood. ABT-263 (Navitoclax), a specific inhibitor of antiapoptotic BCL2 proteins, which is currently being evaluated in clinical trials for the treatment of leukemia and other malignancies, induces a dose-limiting thrombocytopenia. In this study, the relationship between BCL2/BCL-X(L) inhibition, apoptosis, and platelet activation was investigated. Exposure to ABT-263 induced apoptosis but repressed platelet activation by physiologic agonists. Notably, ABT-263 induced an immediate calcium response in platelets and the depletion of intracellular calcium stores, indicating that on BCL2/BCL-X(L) inhibition platelet activation is abrogated because of a diminished calcium signaling. By comparing the effects of ABT-263 and its analog ABT-737 on platelets and leukemia cells from the same donor, we show, for the first time, that these BCL2/BCL-X(L) inhibitors do not offer any selective toxicity but induce apoptosis at similar concentrations in leukemia cells and platelets. However, reticulated platelets are less sensitive to apoptosis, supporting the hypothesis that treatment with ABT-263 induces a selective loss of older platelets and providing an explanation for the transient thrombocytopenia observed on ABT-263 treatment.
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
authors.forename: Meike
authors.initials: M
authors.lastname: Vogler
authors.forename: Hassan A
authors.initials: HA
authors.lastname: Hamali
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Sun
authors.forename: Edward T W
authors.initials: ET
authors.lastname: Bampton
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.forename: Roger T
authors.initials: RT
authors.lastname: Snowden
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000814:Aniline Compounds / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D020013:Calcium Signaling / Q000187:drug effects*; D015870:Gene Expression; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009596:Nitrophenols / Q000009:adverse effects / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced; D034061:Thrombopoiesis; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C528561:navitoclax