Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation

摘要: For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors currently under investigation for the treatment a broad spectrum cancer diseases. However, one clinical drawback is class-specific toxicity unselective limiting their full anticancer potential. Selective targeting individual isozymes in defined tumor entities may therefore be an attractive alternative approach. We have previously identified family member 8 (HDAC8) novel target childhood neuroblastoma. Using small-molecule we now demonstrate selective inhibition HDAC8 exhibits antineuroblastoma activity without two xenograft mouse models MYCN oncogene-amplified In contrast, inhibitor vorinostat was more toxic same models. HDAC8-selective induced cell cycle arrest differentiation vitro vivo. Upon combination with acid, significantly enhanced, demonstrated by elongated neurofilament-positive neurites upregulation NTRK1. Additionally, oncogene expression downregulated growth markedly reduced Mechanistic studies suggest cAMP-response element-binding protein (CREB) links HDAC8- acid-mediated gene transcription. conclusion, HDAC-selective can effective tumors exhibiting isozyme-dependent vivo combined differentiation-inducing agents.