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DOI: 10.1055/s-0033-1343645
Selective inhibition of Histone Deacetylase 8 as a novel therapeutic strategy for the treatment of high-risk neuroblastoma
Aims: Expression studies of primary neuroblastoma samples from the German Neuroblastoma Trial revealed histone deacetylase 8 (HDAC8) to be upregulated in stage 4 patients, associated with a significantly worse prognosis. Here, we investigated the anti-neuroblastoma activity of HDAC8-selective inhibitors (HDAC8i) in vitro and in vivo.
Methods: Treatment of neuroblastoma cell lines and mouse xenografts were used to evaluate the therapeutic potential of HDAC8i. Selectivity for HDAC8 was verified by absence of off-target acetylation in Western Blot at the relevant in vitro and in vivo administration of HDAC8i. In vivo maximal tolerable doses (MTDs) were determined by toxicity studies.
Results: HDAC8i treatment in vitro induced the expression of TrkA, neurofilament and CDK-inhibitor p21Waf-1/Cip-1 and clearly decreased cell population growth. Long term treatment resulted in tumor cell death. Treatment of BE(2)-C xenografted animals with HDAC8i significantly retarded tumor growth compared to control groups (p < 0.001).
Conclusion: Our data show that the selective inhibition of HDAC8 with small molecule compounds provides a novel therapeutic strategy to be effective on NB in vivo.