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  • 1
    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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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; INHIBITOR ; tumor ; TUMOR-CELLS ; AGENTS ; BLOOD ; CELL ; COMBINATION ; Germany ; IN-VIVO ; THERAPY ; TOXICITY ; VITRO ; VIVO ; GENE-EXPRESSION ; PROTEIN ; transcription ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; NITRIC-OXIDE ; TRANSCRIPTION FACTOR ; T cell ; T cells ; T-CELL ; T-CELLS ; treatment ; ALPHA ; TRANSCRIPTION FACTORS ; leukemia ; CANCER-PATIENTS ; OXIDATIVE STRESS ; PERIPHERAL-BLOOD ; TUMOR CELLS ; TRAIL ; TNF-ALPHA ; TRAIL-INDUCED APOPTOSIS ; LEUKEMIA-CELLS ; INHIBITORS ; MALIGNANT-CELLS ; PROGRAM ; RE ; INCREASE ; TUMOR-CELL ; RESISTANT ; CANCER-TREATMENT ; in vivo ; peripheral blood ; viability ; PROSTAGLANDIN E-2 PRODUCTION ; SCUTELLARIAE-RADIX ; SKIN INFLAMMATION
    Abstract: TNF alpha has previously been used in anticancer therapy. However, the therapeutic application of TNF alpha was largely limited due to its general toxicity and the fact that it activates the NF-kappa B-family transcription factors, which are proinflammatory and antiapoptotic. To overcome this problem in vitro, specific NF-kappa B inhibitors or transcription or protein synthesis inhibitors such as actinomycin D and cycloheximide are usually used in combination to increase TNF alpha killing of tumor cells. However, these agents also cause harmful side effects in vivo. We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-kappa B activity by shifting TNF alpha-induced free radical (.) O-2(-) to a more reduced nonradical product, H2O2, and thereby sensitizes TNF alpha-resistant leukemia cells to TNF alpha-induced apoptosis. Importantly, wogonin does not affect the viability of normal peripheral blood T cells. Wogonin also sensitizes TRAIL-induced apoptosis. Our data suggest a potential use of wogonin as a TNF alpha, or TRAIL adjuvant for cancer treatment. Our data also demonstrate how a herbal compound enhances killing of tumor cells with reduced side effects compared with other treatments
    Type of Publication: Journal article published
    PubMed ID: 16931628
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  • 3
    Keywords: CANCER ; CELLS ; IN-VITRO ; INHIBITOR ; BLOOD ; CELL ; Germany ; MODEL ; MODELS ; THERAPY ; VITRO ; ENZYMES ; GENE ; SAMPLE ; SAMPLES ; DRUG ; DIFFERENTIATION ; LINES ; PATIENT ; COMPLEX ; RESPONSES ; DNA ; CELL-LINES ; bone marrow ; BONE-MARROW ; MALIGNANCIES ; PATTERNS ; DIFFERENCE ; CELL-LINE ; leukemia ; DNA methylation ; PATHOGENESIS ; METHYLATION ; HEMATOLOGIC MALIGNANCIES ; DNA methyltransferase ; MYELODYSPLASTIC SYNDROME ; 5-azacytidine ; INHIBITORS ; MALIGNANCY ; ONCOLOGY ; PATTERN ; THERAPIES ; DEMETHYLATION ; ENZYME ; analysis ; USA ; DRUGS ; DECITABINE ; BONE ; cancer research ; AGREEMENT ; 5-AZA-2'-DEOXYCYTIDINE ; DNA-METHYLATION ; azacytidine ; MARROW ; epigenetic ; DNA METHYLATION PATTERNS ; METHYLTRANSFERASE INHIBITORS
    Abstract: Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be established. Both drugs have been shown the ability to deplete DNA methyltransferase enzymes and to induce DNA demethylation and epigenetic reprogramming in vitro. However, drug-induced methylation changes have remained poorly characterized in patients and therapy-related models. We have now analyzed azacytidine-induced demethylation responses in myeloid leukemia cell lines. These cells showed remarkable differences in the drug-induced depletion of DNA methyltransferases that coincided with their demethylation responses. In agreement with these data, DNA methylation analysis of blood and bone marrow samples from MDS patients undergoing azacytidine therapy also revealed substantial differences in the epigenetic responses of individual patients. Significant, transient demethylation could be observed in 3 of 6 patients and affected many hypermethylated loci in a complex pattern. Our results provide important proof-of-mechanism data for the demethylating activity of azacytidine in MDS patients and provide detailed insight into drug-induced demethylation responses
    Type of Publication: Journal article published
    PubMed ID: 18790780
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; CELL ; Germany ; FOLLOW-UP ; GENERATION ; INFORMATION ; DISEASE ; RISK ; HYBRIDIZATION ; DNA ; prognosis ; RISK-FACTORS ; BIOLOGY ; PROGRESSION ; cytogenetics ; MALIGNANCIES ; risk factors ; RISK FACTOR ; FISH ; INSTABILITY ; EVOLUTION ; POOR-PROGNOSIS ; MYELODYSPLASTIC SYNDROME ; HUMAN CANCER ; TUMORIGENESIS ; ACUTE MYELOID-LEUKEMIA ; CHROMOSOMAL INSTABILITY ; development ; CANCERS ; ANEUPLOIDY ; outcome ; CELL BIOLOGY ; CD34 ; Follow up
    Abstract: Chromosomal instability (CIN), defined by an elevated frequency of the occurrence of novel chromosomal aberrations, is strongly implicated in the generation of aneuploidy, one of the hallmarks of human cancers. As for aneuploidy itself, the role of CIN in the evolution and progression of malignancy is a matter still open to debate. We investigated numerical as well as structural CIN in primary CD34-positive cells by determining the cell-to-cell variability of the chromosome content using fluorescence-in situ-hybridization (FISH). Thereby, CIN was measured in 65 patients with myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML) and control subjects. Among MDS patients, a subgroup with elevated levels of CIN was identified. At a median follow-up of 17.2 months, all patients within this 'high CIN' subgroup had died or progressed to AML, while 80% of MDS patients with normal CIN levels had stable disease (P 〈 0.001). Notably, there was no statistically significant difference between 'normal CIN' and 'high CIN' MDS patients regarding established risk factors. Hence, elevated CIN levels were associated with poor outcome, and our method provided additional prognostic information beyond conventional cytogenetics. Furthermore, in all three MDS patients for whom serial measurements were available, development of AML was preceded by increasing CIN levels. In conclusion, elevated CIN levels may be valuable as an early indicator of poor prognosis in MDS, hence corroborating the concept of CIN as a driving force in tumour progression
    Type of Publication: Journal article published
    PubMed ID: 19754665
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; SURVIVAL ; tumor ; CELL ; Germany ; human ; KINASE ; PATHWAY ; TOXICITY ; DEATH ; DISEASE ; LONG-TERM ; PROTEIN ; PROTEINS ; DRUG ; cell line ; TUMORS ; LINES ; PATIENT ; ACTIVATION ; MECHANISM ; FAMILY ; mechanisms ; T-CELLS ; CELL-LINES ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; SUPPRESSION ; treatment ; NO ; MALIGNANCIES ; MEMBRANE ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MODULATION ; LYMPHOCYTES ; DERIVATIVES ; CYTOCHROME-C ; MITOCHONDRIA ; CANCER-PATIENTS ; CONSTITUTIVE ACTIVATION ; side effects ; CANCER PATIENTS ; cell lines ; HEMATOLOGIC MALIGNANCIES ; ANTICANCER DRUGS ; Bcl-2 ; molecular ; MALIGNANCY ; ONCOLOGY ; PROGRAM ; MOLECULAR-MECHANISM ; RE ; FAMILIES ; MAPK ; development ; acute lymphoblastic leukemia ; MOLECULAR-MECHANISMS ; JNK ; EVENTS ; ERK ; BIOLOGICAL-ACTIVITY ; USA ; DRUGS ; CANDIDATE ; COMPOUND ; IMPROVEMENT ; improvement of ; anticancer drug ; BCL-2 FAMILY ; CANDIDATES ; kinase activity ; p38 ; bid ; P38 MAP KINASE
    Abstract: With an increasing cancer rate worldwide, there is an urgent quest for the improvement of anticancer drugs. One of the main problems of present chemotherapy in treatment of tumor patients is the toxicity of drugs. Most of the existent anticancer drugs, unfortunately, attack also proliferating normal cells. In recent years, traditional Chinese herbal remedies have gradually game considerable attention as a new source of anticancer drugs. Although their healing mechanisms are still largely unknown, some of the drugs have been used to help cancer patients fight their disease at reduced side effects compared to other treatments. In our study, we show that Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia, induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Investigation of the molecular mechanisms by which Roc kills tumors revealed that it induces a consistent activation of the stress-response mitogen-activated protein kinase (MAPK) p38 accompanied with a long-term suppression of the survival MAPK extracellular signal-regulated kinase. These events affect proapoptotic Bcl-2 family proteins leading to depolarization of the mitochondrial membrane potential and trigger caspase-mediated apoptosis involving caspase-9, -8, -3 and -2. Importantly, Roc shows no effects on MAPKs in normal lymphocytes and therefore has no or very low toxicity on healthy cells. Up to now, more than 50 different Roe derivatives have been isolated from Aglaia. Our study suggests that Roc derivatives may be promising candidates for the development of new drugs against hematologic malignancies. (C) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17565740
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