Synergistic antileukemic therapies in NOTCH1-induced T-ALL.
Proc Natl Acad Sci U S A
; 114(8): 2006-2011, 2017 02 21.
Article
em En
| MEDLINE
| ID: mdl-28174276
ABSTRACT
The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation-mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biossíntese de Proteínas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Resistencia a Medicamentos Antineoplásicos
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Inibidores Enzimáticos
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Receptor Notch1
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Secretases da Proteína Precursora do Amiloide
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article