Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199
Autor: | Philippe Bouillet, Stefan P Glaser, Seong Lin Khaw, Delphine Merino, David C.S. Huang, Andrew W. Roberts, Mary Ann Anderson |
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Rok vydání: | 2013 |
Předmět: |
Cancer Research
Myeloid Chronic lymphocytic leukemia Blotting Western Apoptosis chemistry.chemical_compound Mice Bcl-2-associated X protein Proto-Oncogene Proteins medicine Tumor Cells Cultured Animals Humans Myeloid Cells B cell Adaptor Proteins Signal Transducing Cell Proliferation bcl-2-Associated X Protein Mice Knockout B-Lymphocytes Sulfonamides Navitoclax biology Bcl-2-Like Protein 11 Cell growth Tumor Suppressor Proteins Membrane Proteins Hematology medicine.disease Bridged Bicyclo Compounds Heterocyclic Flow Cytometry Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays Healthy Volunteers Leukemia medicine.anatomical_structure bcl-2 Homologous Antagonist-Killer Protein Oncology chemistry Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm Immunology biology.protein Cancer research Apoptosis Regulatory Proteins Bcl-2 Homologous Antagonist-Killer Protein |
Zdroj: | Leukemia. 28(6) |
ISSN: | 1476-5551 |
Popis: | Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent. |
Databáze: | OpenAIRE |
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