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  • 1
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    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; DRUG ; DIFFERENTIATION ; INDUCTION ; ACID ; NERVOUS-SYSTEM ; ASSAY ; CANCER-CELLS ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; p21(waf1) ; neuroblastoma ; INVITRO ; LEUKEMIA-CELLS ; ONCOLOGY ; CHILDHOOD ; RE ; medulloblastoma ; cell proliferation ; ASSAYS ; pharmacology ; USA ; anticancer drug ; childhood cancer ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; HKI46F08
    Abstract: Embryonic childhood cancer such as neuroblastoma and medulloblastoma are still a therapeutic challenge requiring novel treatment approaches. Here, we investigated the antitumoral effects of HKI 46F08, a novel trifluoromethyl ketone histone deacetylase (HDAC) inhibitor with a nonhydroxamic acid type structure. HKI 46F08 inhibits in-vitro HDAC activity in cell-free assays with a half maximal inhibitory concentration of 0.6 mu mol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 mu mol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 mu mol/l. HKI 461708 efficiently arrests tumor cell proliferation, represses clonogenic growth and induces differentiation and apoptosis in both MYCN-amplified and nonamplified neuroblastoma cells. In summary, we identified HKI 48F08 as a structural novel, potent HDAC inhibitor with strong antitumoral activity against embryonic childhood cancer cells in the low micromolar range
    Type of Publication: Journal article published
    PubMed ID: 18765999
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  • 3
    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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  • 4
    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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  • 5
    Keywords: EXPRESSION ; IDENTIFICATION ; CANCER-CELLS ; NATURAL-KILLER-CELLS ; HISTONE DEACETYLASE INHIBITORS ; MESSENGER-RNA STABILITY ; SODIUM VALPROATE ; NKG2D ligands ; CYTOTOXICITY RECEPTOR NKP30 ; CHAIN-B
    Abstract: Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7-family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6 we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and mRNA expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after siRNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells, which has implications for potential cancer treatments combining immunotherapy with HDACi.
    Type of Publication: Journal article published
    PubMed ID: 23801635
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  • 6
    Abstract: MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
    Type of Publication: Journal article published
    PubMed ID: 23625969
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  • 7
    Keywords: INHIBITOR ; CLASSIFICATION ; GENE-EXPRESSION ; transcription ; RECRUITMENT ; HISTONE DEACETYLASE ; N-MYC ; B-CELL LYMPHOMAS ; HIGH-RISK NEUROBLASTOMA ; PEDIATRIC SOLID TUMORS
    Abstract: Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as HDAC inhibitors. GRHL1, a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome-wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN co-localized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation and retarded xenograft growth in mice. GRHL1 knock-down in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 24419085
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  • 8
    Keywords: UP-REGULATION ; COLON-CANCER CELLS ; SUBSTRATE-SPECIFICITY ; BIOLOGICAL EVALUATION ; GENE-TRANSCRIPTION ; NEGATIVE REGULATION ; SCHISTOSOMA-MANSONI ; MYELOPROLIFERATIVE NEOPLASMS ; HISTONE DEACETYLASE 8 ; ISOFORM-SELECTIVE INHIBITORS
    Abstract: Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.
    Type of Publication: Journal article published
    PubMed ID: 26013035
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  • 9
    Abstract: The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.
    Type of Publication: Journal article published
    PubMed ID: 25915736
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  • 10
    Abstract: The "Pediatric Targeted Therapy" (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p-AKT, p-ERK, p-S6, p-EGFR, PDGFR-alpha/beta, p53, and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included. n=61/145 (42%) cases were elegible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the H-Score (0-300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were HDACs (83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%), and PI3K/mTOR (36.1%). Follow-up revealed partial or full implementation of PTT results in treatment decision making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 26445087
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