The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Cycle
/ drug effects
Cell Line, Tumor
Cyclopentanes
/ pharmacology
Enzyme Inhibitors
/ pharmacology
Humans
Mice
NEDD8 Protein
/ antagonists & inhibitors
Neuroblastoma
/ drug therapy
Pyrimidines
/ pharmacology
Tumor Suppressor Protein p53
/ metabolism
cell cycle
cullin–ring ligase
pevonedistat
rereplication
ubiquitination
xenograft
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
18 Jun 2021
18 Jun 2021
Historique:
received:
29
03
2021
revised:
11
06
2021
accepted:
14
06
2021
entrez:
2
7
2021
pubmed:
3
7
2021
medline:
14
7
2021
Statut:
epublish
Résumé
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 (p53
Identifiants
pubmed: 34207315
pii: ijms22126565
doi: 10.3390/ijms22126565
pmc: PMC8234433
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Cyclopentanes
0
Enzyme Inhibitors
0
NEDD8 Protein
0
NEDD8 protein, human
0
Pyrimidines
0
Tumor Suppressor Protein p53
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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