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ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib.
- Source :
-
Experimental hematology [Exp Hematol] 2012 May; Vol. 40 (5), pp. 367-78.e2. Date of Electronic Publication: 2012 Jan 10. - Publication Year :
- 2012
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Abstract
- Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients.<br /> (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antigens, CD34 analysis
Apoptosis Regulatory Proteins physiology
Bcl-2-Like Protein 11
Benzamides
Cell Line, Tumor drug effects
Down-Regulation drug effects
Drug Resistance, Neoplasm drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Hematopoietic Stem Cells enzymology
High-Temperature Requirement A Serine Peptidase 2
Humans
Imatinib Mesylate
K562 Cells drug effects
Membrane Proteins physiology
Mitochondrial Proteins physiology
Neoplasm Proteins genetics
Neoplastic Stem Cells enzymology
Proto-Oncogene Proteins physiology
Serine Endopeptidases physiology
X-Linked Inhibitor of Apoptosis Protein genetics
Antineoplastic Agents pharmacology
Apoptosis drug effects
Biphenyl Compounds pharmacology
Gene Expression Regulation, Leukemic drug effects
Hematopoietic Stem Cells drug effects
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Neoplasm Proteins biosynthesis
Neoplastic Stem Cells drug effects
Nitrophenols pharmacology
Piperazines pharmacology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Pyrimidines pharmacology
Sulfonamides pharmacology
X-Linked Inhibitor of Apoptosis Protein biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2399
- Volume :
- 40
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Experimental hematology
- Publication Type :
- Academic Journal
- Accession number :
- 22240609
- Full Text :
- https://doi.org/10.1016/j.exphem.2012.01.004