The anti‐tumor activity of the nedd8 inhibitor pevonedistat in neuroblastoma

Jennifer H. Foster, Eveline Barbieri, Linna Zhang, Kathleen A. Scorsone, Myrthala Moreno‐smith, Peter Zage, Terzah M. Horton

Research output: Contribution to journalArticlepeer-review

Abstract

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin– RING ligase (CRL) proteins involved in the degradation of short‐lived regulatory proteins, including those involved with cell‐cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti‐tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild‐type p53 (p53si‐p53) underwent G2‐M cell‐cycle arrest with rereplication, whereas p53 wild‐type (p53WT) cell lines underwent G0‐G1 cell‐cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8‐activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

Original languageEnglish (US)
Article number6565
JournalInternational journal of molecular sciences
Volume22
Issue number12
DOIs
StatePublished - Jun 2 2021

Keywords

  • Cell cycle
  • Cullin–ring ligase
  • Pevonedistat
  • Rereplication
  • Ubiquitination
  • Xenograft

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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