Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
Sci Transl Med
; 5(171): 171ra17, 2013 Feb 06.
Article
em En
| MEDLINE
| ID: mdl-23390247
ABSTRACT
Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Ativação Transcricional
/
Núcleo Celular
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MAP Quinases Reguladas por Sinal Extracelular
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Proteínas Proto-Oncogênicas c-akt
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Fatores de Transcrição Forkhead
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Ligante Indutor de Apoptose Relacionado a TNF
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Compostos Heterocíclicos de 4 ou mais Anéis
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos