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.
Subject(s)
Histone Deacetylases/metabolism , Neuroblastoma/metabolism , Repressor Proteins/metabolism , Tretinoin/pharmacology , Animals , Blotting, Western , Cell Line, Tumor , Cell Survival/drug effects , Female , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Humans , Hydroxamic Acids , Indoles/pharmacology , Mice , Mice, Nude , Repressor Proteins/genetics , Xenograft Model Antitumor AssaysABSTRACT
Members of the histone deacetylase (HDAC) family exhibit great promise as potential drug targets in pediatric tumors including neuroblastoma, medulloblastoma, ependymoma and Ewing's sarcoma. HDAC inhibitors of various structural classes have shown anti-tumoral effects in pre-clinical pediatric tumor models as single agents or in combination treatments. Suberoylanilidehydroxamic acid (SAHA=vorinostat) is the most clinical advanced compound of the class and was approved by the US FDA in October 2006 for the treatment of refractory cutaneous T-cell lymphoma. In this phase I/II trial, pediatric patients with relapsed solid tumors, lymphoma or leukemias are treated according to an individualized dose escalation concept ensuring each individual patient to receive his optimal dose with respect to toxicity and efficacy. The study is accompanied by an extensive pharmacokinetic, pharmacodynamic and biomarker program.
Subject(s)
Antineoplastic Agents/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Leukemia/drug therapy , Lymphoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasms/drug therapy , Administration, Oral , Adolescent , Antineoplastic Agents/pharmacokinetics , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Histone Deacetylase Inhibitors/pharmacokinetics , Humans , Hydroxamic Acids/pharmacokinetics , Leukemia/blood , Long-Term Care , Lymphoma/blood , Male , Neoplasm Recurrence, Local/blood , Neoplasms/blood , VorinostatABSTRACT
Neuroblastoma is an embryonic tumor of the sympathetic nervous system which represents one of the most common malignancies in early childhood. Its clinical and biological behavior show a remarkable heterogeneity, ranging from spontaneous regression to inexorable progression with a fatal outcome. This review summarizes the clinical risk stratification and treatment options. An extensive overview of the role of imaging during the course of the disease and typical imaging findings in all imaging modalities are demonstrated.
Subject(s)
Diagnostic Imaging , Neuroblastoma/diagnosis , Child, Preschool , Combined Modality Therapy , Disease Progression , Female , Humans , Infant , Male , Neoplasm Regression, Spontaneous , Neoplasm Staging , Neuroblastoma/pathology , Neuroblastoma/therapy , Prognosis , RegistriesABSTRACT
Histone deacetylases (HDACs) are an emerging class of novel anti-cancer drug targets. Recently, studies in adult cancers and in neuroblastoma have shown that individual HDAC family members are aberrantly expressed in tumors and correlate with disease stage and prognosis. In neuroblastoma, knockdown of individual HDAC family members causes distinct phenotypes ranging from differentiation to apoptosis. HDACs are involved in controlling MYCN function and are upregulated in chemotherapy-resistant neuroblastoma cells. Treatment with unselective pan-HDAC inhibitors causes cell cycle arrest, differentiation, apoptosis, and inhibition of clonogenic growth of neuroblastoma cells, and restores susceptibility to chemotherapy treatment. The molecular mechanisms mediating the anti-cancer effects of HDAC inhibitors on neuroblastoma cells are incompletely understood and involve targeting of aberrant epigenetic repression of tumor suppressor genes, activation of developmental differentiation pathways, as well as changing the acetylation level and function of non-histone proteins. In neuroblastoma mouse models, unselective HDAC inhibitors demonstrate anti-tumoral effects. First phase I clinical trials in children with refractory cancers using HDAC inhibitors depsipeptide and the recently approved vorinostat are underway. This review summarizes our current knowledge about classical HDAC family members as novel drug targets for neuroblastoma therapy and discusses the potential role of next generation, selective HDAC inhibitors.
