Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism.
Int J Cancer
; 131(11): 2693-703, 2012 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-22488249
Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy and pharmacodynamics of alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we report that alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established, suggesting that Aurora A inhibition may be a promising strategy to increase the efficacy of ara-C. Accordingly, alisertib significantly potentiated the antileukemic activity of ara-C in both AML cell lines and primary blasts. Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the alisertib/ara-C combination, indicating that it is an important regulator of sensitivity to these agents. In vivo studies demonstrated that alisertib significantly augmented the efficacy of ara-C without affecting its pharmacokinetic profile and led to the induction of p27 and BIM. Our collective data indicate that targeting Aurora A with alisertib represents a novel approach to increase the efficacy of ara-C that warrants further investigation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Azepinas
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Leucemia Mieloide Aguda
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Proteínas Serina-Treonina Quinases
/
Citarabina
/
Fatores de Transcrição Forkhead
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article