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Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.
- Source :
-
Leukemia [Leukemia] 2016 May; Vol. 30 (5), pp. 1086-93. Date of Electronic Publication: 2015 Dec 28. - Publication Year :
- 2016
-
Abstract
- Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. The results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in four of the five cell lines tested. The most striking results were seen with dexamethasone (Dex). Co-treatment of human myeloma cell lines and primary patient samples, with Dex and venetoclax, significantly increased cell death over venetoclax alone in four of the five cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of Dex. This results in alterations in Bim binding to anti-apoptotic proteins. Dex shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity.
- Subjects :
- Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols pharmacology
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Apoptosis Regulatory Proteins metabolism
Bcl-2-Like Protein 11 metabolism
Bridged Bicyclo Compounds, Heterocyclic therapeutic use
Cell Line, Tumor
Dexamethasone therapeutic use
Humans
Melphalan therapeutic use
Middle Aged
Oligopeptides therapeutic use
Protein Binding drug effects
Proto-Oncogene Proteins c-bcl-2 pharmacology
Proto-Oncogene Proteins c-bcl-2 therapeutic use
Sulfonamides therapeutic use
Tumor Cells, Cultured
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Dexamethasone pharmacology
Multiple Myeloma drug therapy
Proto-Oncogene Proteins c-bcl-2 metabolism
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 30
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 26707935
- Full Text :
- https://doi.org/10.1038/leu.2015.350