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  • HDAC inhibitor  (4)
  • 1
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PATHWAY ; THERAPY ; DISEASE ; GENE ; GENES ; PROTEIN ; PROTEINS ; DRUG ; DIFFERENTIATION ; TUMORS ; NEUROBLASTOMA-CELLS ; ACTIVATION ; MECHANISM ; FAMILY ; prognosis ; mechanisms ; cell cycle ; CELL-CYCLE ; CYCLE ; MEMBERS ; SUSCEPTIBILITY ; ANTITUMOR-ACTIVITY ; MOUSE ; TRIAL ; TRIALS ; CELL-DEATH ; CLINICAL-TRIALS ; chemotherapy ; MOUSE MODEL ; TARGETS ; CHILDREN ; HDAC inhibitors ; HISTONE DEACETYLASE ; INTERFERON-ALPHA ; REPRESSION ; TRAIL-INDUCED APOPTOSIS ; neuroblastoma ; HDAC ; INHIBITORS ; ADULT ; review ; FAMILIES ; THERAPIES ; tumor suppressor gene ; EPIGENETICS ; CANCERS ; valproic acid ; Phase I ; SODIUM VALPROATE ; MALIGNANT PHENOTYPE ; NUCLEAR EXPORT ; drug targets ; DRUG-TARGET ; HDAC inhibitor
    Abstract: 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 antitumoral 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
    Type of Publication: Journal article published
    PubMed ID: 19199971
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; INHIBITOR ; tumor ; CELL ; Germany ; PHASE-I ; THERAPY ; LUNG-CANCER ; DEATH ; DISEASE ; DISEASES ; GENE ; GENES ; DRUG ; TUMORS ; MICE ; MESSENGER-RNA EXPRESSION ; FAMILY ; MEMBERS ; BREAST-CANCER ; TRIAL ; TRIALS ; CLINICAL-TRIALS ; CANCER-CELLS ; TARGETS ; HDAC inhibitors ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; HDAC ; INHIBITORS ; SINGLE ; review ; FAMILIES ; IV ; CLASS-II ; development ; PHASE ; COMPOUND ; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA ; REFRACTORY SOLID TUMORS ; VIVO ANTITUMOR-ACTIVITY ; drug targets ; DRUG-TARGET ; HDAC inhibitor ; CONTROLS CHONDROCYTE HYPERTROPHY
    Abstract: Histone deacetylases comprise a family of 18 genes, which are grouped into classes I-IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as "classical" HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase 1 trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18824292
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  • 3
    Keywords: GROWTH ; CELL LUNG-CANCER ; PHASE-I ; ASSAY ; MONONUCLEAR-CELLS ; HUMAN SERUM ; SUBEROYLANILIDE HYDROXAMIC ACID ; HDAC inhibitor ; SAHA ; RITONAVIR
    Abstract: Vorinostat (suberoylanilide hydroxamic acid) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. Intracellular access of vorinostat is essential to exert its epigenetic effects. Therefore, we studied the relationship between vorinostat extracellular (plasma) and intracellular (peripheral blood mononuclear cells, PBMCs) concentration and assessed its concentration-effect relationship by HDAC activity testing. Assays were developed and validated for the low nanomolar quantification of vorinostat and two inactive metabolites in human plasma and PBMCs. For the vorinostat extraction from plasma and PBMCs solid-phase extraction and liquid-liquid extraction methods were applied. Extraction recoveries ranged from 88.6% to 114.4% for all analytes and extraction methods. Extracts were chromatographed on a Phenomenex Luna column isocratically (plasma) or by gradient (PBMCs) consisting of acidic ammonium acetate, acetonitrile, and methanol. The analytes were quantified using deuterated internal standards and positive electrospray tandem mass spectrometry (multiple reaction monitoring) with lower limits of quantification of 11.0 ng/mL (plasma) and 0.1 ng/3 x 10(6) cells (PBMCs). The calibrated ranges were linear for vorinostat in plasma 11.0-1100 (11,000) ng/mL (metabolites) and PBMCs 0.1-10.0 ng/3 x 10(6) cells with correlation coefficients 〉0.99, an overall accuracy varying between -6.7% and +3.8% in plasma, -8.1% and -1.5% in PBMCs, and an overall precision ranging from 3.2% to 6.1% in plasma and 0.8% to 4.0% in PBMCs (SD batch-to-batch). The application to blood samples from healthy volunteers incubated with vorinostat revealed accumulation of vorinostat in PBMCs, effective intracellular HDAC inhibition at therapeutic vorinostat concentrations and a direct vorinostat concentration dependency to HDAC inhibition.
    Type of Publication: Journal article published
    PubMed ID: 24636840
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  • 4
    Keywords: IN-VITRO ; PHASE-I ; NERVOUS-SYSTEM ; INDUCED APOPTOSIS ; POOR-PROGNOSIS ; COLON-CANCER CELLS ; SOLID TUMORS ; valproic acid ; HDAC inhibitor ; GENETIC PROFILES
    Abstract: Medulloblastomas are the most common malignant brain tumors in childhood. Emerging evidence suggests that medulloblastoma comprises at least four distinct diseases (WNT, SHH, Group 3 and 4) with different biology, clinical presentation, and outcome, with especially poor prognosis in Group 3. The tight connection of biology and clinical behavior in patients emphasizes the need for subgroup-specific preclinical models in order to develop treatments tailored to each subgroup. Herein we report on the novel cell line HD-MB03, isolated from tumor material of a patient with metastasized Group 3 medulloblastoma, and preclinical testing of different histone deacetylase inhibitors (HDACis) in this model. HD-MB03 cells grow long term in vitro and form metastatic tumors in vivo upon orthotopic transplantation. HD-MB03 cells reflect the original Group 3 medulloblastoma at the histological and molecular level, showing large cell morphology, similar expression patterns for markers Ki67, p53, and glial fibrillary acidic protein (GFAP), a gene expression profile most closely matching Group 3 medulloblastomas, and persistence of typical molecular alterations, i.e., isochromosome 17q [i(17q)] and MYC amplification. Protein expression analysis of HDACs 2, 5, 8, and 9 as well as the predictive marker HR23B showed intermediate to strong expression, suggesting sensitivity to HDACis. Indeed, treatment with HDACis Helminthosporium carbonum (HC)-toxin, vorinostat, and panobinostat revealed high sensitivity to this novel drug class, as well as a radiation-sensitizing effect with significantly increased cell death upon concomitant treatment. In summary, our data indicate that HD-MB03 is a suitable preclinical model for Group 3 medulloblastoma, and HDACis could represent a therapeutic option for this subgroup.
    Type of Publication: Journal article published
    PubMed ID: 23054560
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