The Use of the NEDD8 Inhibitor MLN4924 (Pevonedistat) in a Cyclotherapy Approach to Protect Wild-type P53 Cells from MLN4924 Induced Toxicity

Overview

Journal Sci Rep

Specialty Science

Date 2016 Dec 1

PMID 27901050

Citations 13

Authors

Lara J Bou Malhab

Simon Descamps

Benedicte Delaval

Dimitris P Xirodimas

Affiliations

Soon will be listed here.

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.

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