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Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo.
- Source :
-
Blood [Blood] 2016 Mar 03; Vol. 127 (9), pp. 1128-37. Date of Electronic Publication: 2015 Dec 16. - Publication Year :
- 2016
-
Abstract
- Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Caspases metabolism
Cell Cycle Checkpoints drug effects
Cell Line, Tumor
Cell Separation
Cell Survival drug effects
Cyclopentanes pharmacology
Enzyme Inhibitors pharmacology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Humans
Lymphoma, Mantle-Cell genetics
Lymphoma, Mantle-Cell pathology
Mice, SCID
NEDD8 Protein
NF-kappa B metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Pyrimidines pharmacology
Rituximab pharmacology
Small Molecule Libraries pharmacology
Small Molecule Libraries therapeutic use
Ubiquitins metabolism
Cyclopentanes therapeutic use
Enzyme Inhibitors therapeutic use
Lymphoma, Mantle-Cell drug therapy
Pyrimidines therapeutic use
Rituximab therapeutic use
Ubiquitins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 127
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 26675347
- Full Text :
- https://doi.org/10.1182/blood-2015-04-640920