PUBLICATION
The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity
- Authors
- Malhab, L.J., Descamps, S., Delaval, B., Xirodimas, D.P.
- ID
- ZDB-PUB-161203-15
- Date
- 2016
- Source
- Scientific Reports 6: 37775 (Journal)
- Registered Authors
- Keywords
- Biochemistry, Cancer
- MeSH Terms
-
- Apoptosis/drug effects
- Cell Line, Tumor
- Cyclopentanes/pharmacology*
- HCT116 Cells
- Humans
- NEDD8 Protein/antagonists & inhibitors*
- Pyrimidines/pharmacology*
- Tumor Suppressor Protein p53/metabolism*
- Ubiquitins/metabolism
- PubMed
- 27901050 Full text @ Sci. Rep.
Citation
Malhab, L.J., Descamps, S., Delaval, B., Xirodimas, D.P. (2016) The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity. Scientific Reports. 6:37775.
Abstract
Targetting the ubiquitin pathway is an attractive strategy for cancer therapy. The inhibitor of the ubiquitin-like molecule NEDD8 pathway, MLN4924 (Pevonedistat) is in Phase II clinical trials. Protection of healthy cells from the induced toxicity of the treatment while preserving anticancer efficacy is a highly anticipated outcome in chemotherapy. Cyclotherapy was proposed as a promising approach to achieve this goal. We found that cytostatic activation of p53 protects cells against MLN4924-induced toxicity and importantly the effects are reversible. In contrast, cells with mutant or no p53 remain sensitive to NEDD8 inhibition. Using zebrafish embryos, we show that MLN4924-induced apoptosis is reduced upon pre-treatment with actinomycin D in vivo. Our studies show that the cellular effects of NEDD8 inhibition can be manipulated based on the p53 status and that NEDD8 inhibitors can be used in a p53-based cyclotherapy protocol to specifically target cancer cells devoid of wild type p53 function, while healthy cells will be protected from the induced toxicity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping