BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation.

@article{Vogler2011BCL2BCLXLII,
  title={BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation.},
  author={Meike Vogler and Hassan A. Hamali and Xiao-ming Sun and Edward T. W. Bampton and David Dinsdale and Roger T. Snowden and Martin J. S. Dyer and Alison H. Goodall and Gerald M. Cohen},
  journal={Blood},
  year={2011},
  volume={117 26},
  pages={
          7145-54
        }
}
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… 

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References

SHOWING 1-10 OF 51 REFERENCES

Bcl-2 family proteins are essential for platelet survival

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.

Alterations in Bcl‐2/Bax protein levels in platelets form part of an ionomycin‐induced process that resembles apoptosis

The data indicate that platelets may constitute a natural model for the analysis of cytoplasmic events in apoptosis, and mRNA expression of bcl‐2, baxα and p53 in highly purified non‐stimulated platelets is demonstrated.

Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia.

The data indicate that after therapy with ABT-737-related inhibitors, resistant CLL cells might develop in lymph nodes in vivo and that treatment strategies targeting multiple BCL2 antiapoptotic members simultaneously may have synergistic activity.

BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency

In conclusion, platelet lifespan is regulated by a fine balance between anti- and proapoptotic multidomain Bcl-2 family proteins.

Role of caspase in a subset of human platelet activation responses.

Using cell-permeable specific inhibitors, a role for a caspase-3-like protease is demonstrated in the agonist-induced platelet activation events of phosphatidylserine exposure, microparticle release, and cleavage of moesin, a cytoskeletal-membrane linker protein.

Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function.

2 distinct pathways regulating the procoagulant function of platelets are shown, one of which is Bak/Bax- and caspase-dependent and the other is agonist-induced, which was completely eliminated by extracellular calcium chelators or inhibitors of platelet activation.

Constitutive Death of Platelets Leading to Scavenger Receptor-mediated Phagocytosis

A complete and constitutive but caspase-independent program for the specific phagocytic clearance of intact effete platelets, anucleated blood cells of critical importance in health and disease is reported.

Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis.

The hypothesis that formation of the mitochondrial permeability transition pore, a key signaling event during cell death, also plays a critical role in platelet activation is tested and a novel CypD-dependent negative-feedback mechanism regulating arterial thrombosis is suggested.

Comparison of the relative activities of inducing platelet apoptosis stimulated by various platelet-activating agents

It is demonstrated for the first time that thrombin, U46619, and A23187, but not AA, possess stronger activity in inducing platelet apoptosis, and it is found that platelet activation might not necessarily be associated with the occurrence of platelets apoptosis.

Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation.

Inhibition of the calcium-dependent proteinase, calpain, prevented caspase proteolysis, 'apoptotic' substrate cleavage, and platelet microvesiculation, and suggest that cal pain, not caspases, promotes apoptosis-like events during platelet activation.
...