title: Bcl-2 family proteins are essential for platelet survival.
abstract: Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.
authors.affiliation: Department of Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064-6101, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: P M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: S K
authors.initials: SK
authors.lastname: Tahir
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: R M
authors.initials: RM
authors.lastname: Fryer
authors.forename: K R
authors.initials: KR
authors.lastname: Hahn
authors.forename: L A
authors.initials: LA
authors.lastname: Iciek
authors.forename: S J
authors.initials: SJ
authors.lastname: Morgan
authors.forename: M C
authors.initials: MC
authors.lastname: Nasarre
authors.forename: R
authors.initials: R
authors.lastname: Nelson
authors.forename: L C
authors.initials: LC
authors.lastname: Preusser
authors.forename: G A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: M L
authors.initials: ML
authors.lastname: Smith
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: S W
authors.initials: SW
authors.lastname: Elmore
authors.forename: C
authors.initials: C
authors.lastname: Tse
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010718:Phosphatidylserines; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides