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 effect

SUBMITTER: Malhab LJ 

PROVIDER: S-EPMC5129021 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature