title: The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity.
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.
authors.affiliation: CRBM-CNRS, Cell Biology Research of Montpellier, UMR5237, Montpellier University, 1919 Route de Mende, 34293, Cedex 5, Montpellier, France.
authors.forename: Lara J Bou
authors.initials: LJ
authors.lastname: Malhab
authors.affiliation: CRBM-CNRS, Cell Biology Research of Montpellier, UMR5237, Montpellier University, 1919 Route de Mende, 34293, Cedex 5, Montpellier, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Descamps
authors.affiliation: CRBM-CNRS, Cell Biology Research of Montpellier, UMR5237, Montpellier University, 1919 Route de Mende, 34293, Cedex 5, Montpellier, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Delaval
authors.affiliation: CRBM-CNRS, Cell Biology Research of Montpellier, UMR5237, Montpellier University, 1919 Route de Mende, 34293, Cedex 5, Montpellier, France.
authors.forename: Dimitris P
authors.initials: DP
authors.lastname: Xirodimas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D000075687:NEDD8 Protein / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C539933:pevonedistat