Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines.
Blood
; 112(4): 1424-33, 2008 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-18541724
ABSTRACT
Epigenetic changes have been implicated in silencing several B-cell genes in Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma (HL), and this mechanism has been proposed to promote HRS survival and escape from immunosurveillance. However, the molecular and functional consequences of histone deacetylase (HDAC) inhibition in HL have not been previously described. In this study, we report that the HDAC inhibitor vorinostat induced p21 expression and decreased Bcl-xL levels causing cell-cycle arrest and apoptosis. Furthermore, vorinostat inhibited STAT6 phosphorylation and decreased its mRNA levels in a dose- and time-dependent manner, which was associated with a decrease in the expression and secretion of Thymus and Activation-Regulated Chemokine (TARC/CCL17) and interleukin (IL)-5 and an increase in IP-10 levels. Moreover, vorino-stat inhibited TARC secretion by dendritic cells that were activated by the thymic stromal lymphopoietin (TSLP). Collectively, these data suggest that pharmacologic HDAC inhibition in HL may induce favorable antitumor activity by a direct antiproliferative effect on HRS cells, and possibly by an immune mediated effect by altering cytokine and chemokines secretion in the microenvironment.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Doença de Hodgkin
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Citocinas
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Células Th2
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Fator de Transcrição STAT6
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Quimiocina CCL17
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Ácidos Hidroxâmicos
Limite:
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos