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  • 1
    Keywords: brain ; CANCER ; CELLS ; INHIBITOR ; tumor ; CELL ; Germany ; THERAPY ; DISEASE ; LONG-TERM ; NEW-YORK ; HYBRIDIZATION ; TUMORS ; PATIENT ; primary ; chromosome ; polymorphism ; single nucleotide polymorphism ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; ARRAYS ; CHROMOSOMAL-ABERRATIONS ; genetics ; SNP ; ABERRATIONS ; HUMAN HOMOLOG ; CENTRAL-NERVOUS-SYSTEM ; TRANSLOCATION ; DE-NOVO ; CHILDREN ; FLUORESCENCE ; fluorescence in situ hybridization ; PROTEASOME ; heredity ; TRAIL ; TRAIL-INDUCED APOPTOSIS ; CHROMOSOMES ; in situ hybridization ; SINGLE ; CYTOKINE ; molecular ; ONCOLOGY ; ADULT ; ADULTS ; BRAIN-TUMORS ; HUMAN CANCER ; THERAPIES ; ARRAY ; GRADE ; medulloblastoma ; PRIMITIVE NEUROECTODERMAL TUMORS ; CHEMOTHERAPEUTIC DRUGS ; single-nucleotide ; BASAL-CELL CARCINOMAS ; USA ; RESISTANT ; RARE ; aberration ; chromosomal aberration ; ACUTE MYELOID LEUKEMIAS ; BORTEZOMIB ; CHROMOSOMAL CHANGES ; PARTIAL UNIPARENTAL DISOMY
    Abstract: Medulloblastoma is a malignant invasive embryonal tumor, occurring in children mainly. It is rare in adults (〈 1 % of adult brain tumors), and so comprehensive cytogenetic and molecular biological data on adult medulloblastomas are very limited. Conventional therapies provide disappointing long-term disease control, and new therapeutic options are being tested. We performed comprehensive cytogenetic analyses of an adult medulloblastoma, WHO grade IV, using trypsin-Giemsa staining (GTG-banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH, complemented by molecular karyotyping using high-density single nucleotide polymorphism (SNP) arrays. GTG-banding of 25 metaphases revealed 31 structural chromosomal aberrations, predominantly located on chromosomes 4q, 9q, 10q, l l p, and 20q, which were confirmed by M-FISH. Two novel, so far not described translocations were found: t(4;11)(q25;p15) and t(9;20)(p23;p12). GTG-banding, locus-specific FISH, and M-FISH detected numerical changes of chromosomes 8, 14, 18, 19, 20, 21, and 22. Molecular karyotyping by SNP array confirmed chromosomal changes -2p, -10q, -16q, and -Xq and revealed de novo partial uniparental disomy 1q and 9q. Applying an upcoming therapeutic approach, we found that primary medulloblastoma cells were resistant to TRAIL, a novel anticancer cytokine, but could be efficiently sensitized by cotreatment with the proteasome inhibitor bortezomib. Bortezomib-TRAIL cotreatment may serve as a powerful therapeutic option for medulloblastoma patients. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17954265
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VITRO ; VIVO ; screening ; ENZYMES ; GENE ; GENE-EXPRESSION ; GENES ; METABOLISM ; DIFFERENTIATION ; INDUCTION ; BIOLOGY ; MOLECULAR-BIOLOGY ; IDENTIFICATION ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; CARCINOMA CELLS ; NUMBER ; EFFICIENT ; acetylation ; CARCINOMA-CELLS ; ONCOGENE ; PHENOTYPE ; RECRUITMENT ; specificity ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; REPRESSION ; neuroblastoma ; INHIBITORS ; AGENT ; molecular biology ; molecular ; INCREASE ; LEVEL ; ENZYME ; HISTONE DEACETYLASE INHIBITORS ; HISTONE ACETYLATION ; H4 ; ENGLAND ; amidohydrolase ; STRAIN ; SMALL-MOLECULE ; ACTINOMYCIN-D ; amidohydrolase (HDAH) ; chromone ; histone deacetylase-like ; KETONE INHIBITORS ; LEUKEMIA-CELL LINE ; medium-throughput screening ; p-benzoquinone ; pyran-4-one ; SOPHOROSE LIPIDS ; trifluoromethylketone
    Abstract: HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene,expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development
    Type of Publication: Journal article published
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  • 3
    Keywords: brain ; CELLS ; EXPRESSION ; PATHWAY ; MICE ; MOUSE ; CELL-DEATH ; TUMOR-SUPPRESSOR GENE ; CRE RECOMBINASE ; ANIMAL-MODELS ; MAMMALIAN TARGET ; neurodegeneration ; mTOR ; NIGROSTRIATAL SYSTEM ; MOTOR DEFICITS ; NUCLEOLAR DISRUPTION
    Abstract: Parkinson's disease (PD) is a progressive age-related movement disorder that results primarily from the selective loss of midbrain dopaminergic (DA) neurons. Symptoms of PD can be induced by genetic mutations or by DA neuron-specific toxins. A specific ablation of an essential factor controlling ribosomal RNA transcription, TifIa, in adult mouse DA neurons represses mTOR signaling and leads to progressive neurodegeneration and PD-like phenotype. Using an inducible Cre system in adult mice, we show here that the specific ablation of Pten in adult mouse DA neurons leads to activation of mTOR pathway and is neuroprotective in genetic (TifIa deletion) and neurotoxin-induced (MPTP or 6OHDA) mouse models of PD. Adult mice with DA neuron-specific Pten deletion exhibit elevated expression of tyrosine hydroxylase, a rate-limiting enzyme in the dopamine biosynthesis pathway, associated with increased striatal dopamine content, and increased mRNA levels of Foxa2, Pitx3, En1, Nurr1, and Lmx1b-the essential factors for maintaining physiological functions of adult DA neurons. Pten deletion attenuates the loss of tyrosine hydroxylase-positive cells after 6OHDA treatment, restores striatal dopamine in TifIa-knockout and MPTP-treated mice, and rescues locomotor impairments caused by TifIa loss. Inhibition of Pten-dependent functions in adult DA neurons may represent a promising PD therapy.-Domanskyi, A., Geissler, C., Vinnikov, I. A., Alter, H., Schober, A., Vogt, M. A., Gass, P., Parlato, R., Schutz, G. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models.
    Type of Publication: Journal article published
    PubMed ID: 21593433
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; GENE ; transcription ; CREB ; acetylation ; HISTONE DEACETYLASE INHIBITORS ; SOX4 ; COOPERATE
    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.
    Type of Publication: Journal article published
    PubMed ID: 25695609
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