Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia.
Blood
; 115(18): 3796-800, 2010 May 06.
Article
em En
| MEDLINE
| ID: mdl-20203261
ABSTRACT
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Ubiquitinas
/
Leucemia Mieloide Aguda
/
Ciclopentanos
/
Inibidores de Proteassoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article