ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia
- Author(s)
- Vandenberg, CJ; Cory, S;
- Details
- Publication Year 2013-03-21,Volume 121,Issue #12,Page 2285-2288
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- BH3-only proteins trigger the stress apoptosis pathway and chemical mimetics have great potential for cancer therapy. BH3-only proteins inhibit antiapoptotic members of the Bcl-2 family. Promising BH3 mimetic ABT-737 and the related orally available compound ABT-263 (navitoclax) bind avidly to antiapoptotic Bcl-2, Bcl-x(L), and Bcl-w. However, their interaction with Bcl-x(L) provokes thrombocytopenia, which has proven to be the dose-limiting toxicity. We have tested the efficacy of ABT-199, a new Bcl-2-specific BH3 mimetic, against aggressive progenitor cell lymphomas derived from bitransgenic myc/bcl-2 mice. As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor-bearing mice without causing thrombocytopenia. Both drugs acted rapidly but, contrary to prevailing models, their apoptotic activity did not rely upon the BH3-only protein Bim. When ABT-737 was combined with the proteosome inhibitor bortezomib or CDK inhibitor purvalanol, many treated animals achieved long-term remission.
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTAGONIST ABT-737; ANTITUMOR-ACTIVITY; MULTIPLE-MYELOMA; TRANSGENIC MICE; CELL-DEATH; BCL-2; INHIBITOR; MCL-1; APOPTOSIS
- Research Division(s)
- Molecular Genetics Of Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606065/
- Publisher's Version
- https://doi.org/10.1182/blood-2013-01-475855
- Terms of Use/Rights Notice
- © 2013 by The American Society of Hematology
Creation Date: 2013-03-21 12:00:00