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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2011-8-12
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pubmed:abstractText |
BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2-related proteins. Agents that inhibit Bcl-x(L) induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ib? and glycoprotein VI, and functional down-regulation of integrin ?(IIb)?(3). Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ABT 263,
http://linkedlifedata.com/resource/pubmed/chemical/ABT-737,
http://linkedlifedata.com/resource/pubmed/chemical/Aniline Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Biphenyl Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Collagen,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nitrophenols,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylserines,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Glycoprotein GPIIb-IIIa...,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/adhesion receptor,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein,
http://linkedlifedata.com/resource/pubmed/chemical/platelet membrane glycoprotein VI
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1528-0020
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pubmed:author |
pubmed-author:AlwisImalaI,
pubmed-author:AndrewsRobert KRK,
pubmed-author:DoK HKH,
pubmed-author:GardinerElizabeth EEE,
pubmed-author:HuangDavid C SDC,
pubmed-author:JacksonShaun PSP,
pubmed-author:JarmanKate EKE,
pubmed-author:JosefssonEmma CEC,
pubmed-author:KileBenjamin TBT,
pubmed-author:MasonKylie DKD,
pubmed-author:OnoAkikoA,
pubmed-author:QiaoJianlinJ,
pubmed-author:RobertsAndrew WAW,
pubmed-author:SalemHatem HHH,
pubmed-author:SchoenwaelderSimone MSM,
pubmed-author:WhiteMichael JMJ,
pubmed-author:WillcoxAbbeyA
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pubmed:issnType |
Electronic
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pubmed:day |
11
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pubmed:volume |
118
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1663-74
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pubmed:meshHeading |
pubmed-meshheading:21673344-Aniline Compounds,
pubmed-meshheading:21673344-Animals,
pubmed-meshheading:21673344-Apoptosis,
pubmed-meshheading:21673344-Biphenyl Compounds,
pubmed-meshheading:21673344-Blood Platelets,
pubmed-meshheading:21673344-Blotting, Western,
pubmed-meshheading:21673344-Collagen,
pubmed-meshheading:21673344-Dose-Response Relationship, Drug,
pubmed-meshheading:21673344-Down-Regulation,
pubmed-meshheading:21673344-Hemostasis,
pubmed-meshheading:21673344-Membrane Glycoproteins,
pubmed-meshheading:21673344-Mice,
pubmed-meshheading:21673344-Mice, Inbred C57BL,
pubmed-meshheading:21673344-Microscopy, Electron, Scanning,
pubmed-meshheading:21673344-Nitrophenols,
pubmed-meshheading:21673344-Phosphatidylserines,
pubmed-meshheading:21673344-Piperazines,
pubmed-meshheading:21673344-Platelet Adhesiveness,
pubmed-meshheading:21673344-Platelet Aggregation,
pubmed-meshheading:21673344-Platelet Count,
pubmed-meshheading:21673344-Platelet Glycoprotein GPIIb-IIIa Complex,
pubmed-meshheading:21673344-Platelet Membrane Glycoproteins,
pubmed-meshheading:21673344-Sulfonamides,
pubmed-meshheading:21673344-Thrombocytopenia,
pubmed-meshheading:21673344-Time Factors,
pubmed-meshheading:21673344-bcl-X Protein
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pubmed:year |
2011
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pubmed:articleTitle |
Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets.
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pubmed:affiliation |
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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