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Cancer Res ; 66(14): 7195-202, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16849566

RESUMO

Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic Therapy.


Assuntos
Adenoviridae/fisiologia , Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/metabolismo , Genes MDR/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Terapia Viral Oncolítica/métodos , Neoplasias da Próstata/terapia , Adenoviridae/genética , Proteínas E2 de Adenovirus/genética , Animais , Núcleo Celular/metabolismo , Terapia Combinada , Daunorrubicina/farmacologia , Docetaxel , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Nucleares , Regiões Promotoras Genéticas , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/virologia , Taxoides/farmacologia , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box
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