The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.

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.

• Authors: Tun Kiat Ko, Charles T H Chuah, John W J Huang, King-Pan Ng, S Tiong Ong
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 19 Pg. 9033-8 (Oct 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25333252 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Benzamides
• Bridged Bicyclo Compounds, Heterocyclic
• Piperazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• Sulfonamides
• Imatinib Mesylate
• venetoclax
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Neoplastic Stem Cells (drug effects)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Tumor Stem Cell Assay