Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.1925
Title: The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors
Authors: Ko T.K. 
Chuah C.T. 
Huang J.W.
Ng K.-P. 
Ong S.T. 
Keywords: BCR ABL protein
BH3 protein
imatinib
navitoclax
protein bcl 2
protein bcl xl
protein tyrosine kinase inhibitor
venetoclax
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
aniline derivative
antineoplastic agent
benzamide derivative
fused heterocyclic rings
imatinib
navitoclax
piperazine derivative
protein bcl 2
protein kinase inhibitor
pyrimidine derivative
sulfonamide
Article
blood toxicity
cell death
chronic myeloid leukemia
drug activity
human
human cell
IC50
maximum tolerated dose
protein expression
thrombocyte lifespan
thrombocytopenia
antagonists and inhibitors
apoptosis
cancer stem cell
drug effects
drug resistance
drug screening
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
metabolism
tumor cell line
Aniline Compounds
Antineoplastic Agents
Apoptosis
Benzamides
Bicyclo Compounds, Heterocyclic
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplastic Stem Cells
Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Pyrimidines
Sulfonamides
Tumor Stem Cell Assay
Issue Date: 2014
Citation: Ko T.K., Chuah C.T., Huang J.W., Ng K.-P., Ong S.T. (2014). The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget 5 (19) : 9033-9038. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.1925
Abstract: BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174163
ISSN: 19492553
DOI: 10.18632/oncotarget.1925
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