CRBM-CNRS, Cell Biology Research of Montpellier, UMR5237, Montpellier University, 1919 Route de Mende, 34293, Cedex 5, Montpellier, France.
Sci Rep. 2016 Nov 30;6:37775. doi: 10.1038/srep37775.
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.
靶向泛素途径是癌症治疗的一种有吸引力的策略。泛素样分子 NEDD8 途径的抑制剂 MLN4924（Pevonedistat）正在进行 II 期临床试验。在化疗中，保护健康细胞免受治疗引起的毒性，同时保持抗癌疗效是人们高度期待的结果。周期性化疗被提出是实现这一目标的一种很有前途的方法。我们发现，p53 的细胞生长抑制激活可保护细胞免受 MLN4924 诱导的毒性，重要的是，这种作用是可逆的。相比之下，p53 突变或缺失的细胞仍然对 NEDD8 抑制敏感。我们使用斑马鱼胚胎表明，体内用放线菌素 D 预处理可减少 MLN4924 诱导的细胞凋亡。我们的研究表明，基于 p53 状态，可以操纵 NEDD8 抑制的细胞效应，并且可以在基于 p53 的周期性化疗方案中使用 NEDD8 抑制剂，以专门针对缺乏野生型 p53 功能的癌细胞，而健康细胞将免受诱导的毒性。
