Abstract
For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.
Highlights
The human family of histone deacetylase (HDAC) is grouped into four classes based on their homology to yeast HDACs
We have recently demonstrated that knockdown and inhibition of HDAC family member 8 (HDAC8) in neuroblastoma cell cultures induced cell cycle arrest and differentiation.[15]
HDAC8 expression levels significantly correlated with INSS (International Neuroblastoma Staging System) stage 4 and poor overall survival (Supplementary Figures 1A and B)
Summary
Small-molecule inhibitors of HDAC enzymatic activity bind to the highly conserved catalytic domain and unselectively inhibit the activity of all zinc-dependent HDACs. Vorinostat (SAHA: suberoylanilide hydroxamic acid) was the first HDAC inhibitor to be approved for clinical use by the FDA for the treatment of refractory cutaneous T-cell lymphoma.[8] In several clinical trials, vorinostat was active against leukemia. Response element-binding protein; GEO, Gene Expression Omnibus; GGT, gamma-glutamyltransferase; GPT, glutamic pyruvic transaminase; HDAC, histone deacetylase; HDAC8, HDAC family member 8; H&E, hematoxylin and eosin; INSS, International Neuroblastoma Staging System; MTD, maximum tolerable dose; NEF, neurofilament; NTRK1, neurotrophic tyrosine kinase receptor type 1; OT, glutamic oxaloacetic transaminase; PBMC, peripheral blood mononuclear cells; P-H3, phosphorylated histone 3; SAHA, suberoylanilide hydroxamic acid; TrkA, tropomyosin receptor kinase A; TSA, trichostatin A. HDAC inhibitors is associated with dose-limiting side effects such as thrombocytopenia, fatigue, nausea, diarrhea and anorexia (reviewed in Lane and Chabner[9] and Witt et al.[10])
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