Bcl-xL–inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets
Open Access
- 11 August 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (6), 1663-1674
- https://doi.org/10.1182/blood-2011-04-347849
Abstract
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-xL 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 Ibα and glycoprotein VI, and functional down-regulation of integrin αIIbβ3. 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-xL–inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.Keywords
This publication has 44 references indexed in Scilit:
- Current strategies to target p53 in cancerBiochemical Pharmacology, 2010
- Targeting PI3K signalling in cancer: opportunities, challenges and limitationsNature Reviews Cancer, 2009
- Targeting cancer with small molecule kinase inhibitorsNature Reviews Cancer, 2009
- IAP-targeted therapies for cancerOncogene, 2008
- Oncogenic PI3K deregulates transcription and translationNature Reviews Cancer, 2005
- NF-κB: linking inflammation and immunity to cancer development and progressionNature Reviews Immunology, 2005
- Apoptosis-based therapies for hematologic malignanciesBlood, 2005
- Cancer therapy and p53Current Opinion in Oncology, 1995
- Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistanceCurrent Opinion in Oncology, 1995
- The p53 Tumor-Suppressor GeneThe New England Journal of Medicine, 1992