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1.
Mol Cancer Ther ; 10(10): 1807-17, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21859840

RESUMO

Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-κB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1α. NSC 47147 was shown to decrease levels of p-FADD and NF-κB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell-based assays for the identification of active compounds and the validation of drug-target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy.


Assuntos
Proteína de Domínio de Morte Associada a Fas/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Fatores de Transcrição/metabolismo , Alcaloides/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Biomol Screen ; 15(9): 1063-70, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20855560

RESUMO

Fas-associated protein with death domain (FADD) was originally reported as a proapoptotic adaptor molecule that mediates receptor-induced apoptosis. Recent studies have revealed a potential role of FADD in NF-κB activation, embryogenesis, and cell cycle regulation and proliferation. Overexpression of FADD and its phosphorylation have been associated with the transformed phenotype in many cancers and is therefore a potential target for therapeutic intervention. In an effort to delineate signaling events that lead to FADD phosphorylation and to identify novel compounds that impinge on this pathway, the authors developed a cell-based reporter for FADD kinase activity. The reporter assay, optimized for a high-throughput screen (HTS), measures bioluminescence in response to modulation of FADD kinase activity in live cells. In addition, the potential use of the reporter cell line in the rapid evaluation of pharmacologic properties of HTS hits in mouse models has been demonstrated.


Assuntos
Proteína de Domínio de Morte Associada a Fas/antagonistas & inibidores , Ensaios de Triagem em Larga Escala/métodos , Imagem Molecular/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacologia , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Proteína de Domínio de Morte Associada a Fas/química , Genes Reporter , Humanos , Medições Luminescentes , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Reprodutibilidade dos Testes , Fatores de Tempo
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