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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: International Journal of Cancer, 01 May 2013, Vol.132(9), pp.2200-2208
    Description: Inhibition of histone deacetylase (HDAC) activity as stand‐alone or combination therapy represents a promising therapeutic approach in oncology. The pan‐ or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose‐limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc‐dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT‐116 colon, PC‐3 prostate, MCF‐7 breast and SK‐OV‐3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor‐selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. What's new? Histone deacetylase (HDAC) enzymes influence the regulation of numerous cellular processes, and their inhibition by small molecules has been shown to provide benefits against multiple cancer types. Here, HDAC11, a recently identified member of the HDAC family, was found to play an important role in the control of proliferation and survival pathways in several carcinoma cell lines. The high incidence of the tumors represented suggests that HDAC11 could be a valuable drug target in oncology.
    Keywords: Chromatin Modulation ; Targeted Therapy ; Histone Deacetylase ; Colon Cancer ; Prostate Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: International Journal of Cancer, 01 September 2010, Vol.127(5), pp.1230-1239
    Description: Despite multimodal therapeutic concepts, advanced localized and high‐risk neuroblastoma remains a therapeutic challenge with a long‐term survival rate below 50%. Consequently, new modalities for the treatment of neuroblastoma, ., oncolytic virotherapy are urgently required. H‐1PV is a rodent parvovirus devoid of relevant pathogenic effects in infected adult animals. In contrast, the virus has oncolytic properties and is particularly cytotoxic for transformed or tumor‐derived cells of various species including cells of human origin. Here, a preclinical assessment of the application of oncolytic H‐1PV for the treatment of neuroblastoma cells was performed. Infection efficiency, viral replication and lytic activity of H‐1PV were analyzed in 11 neuroblastoma cell lines with different MYCN status. Oncoselectivity of the virus was confirmed by the infection of short term cultures of nonmalignant infant cells of different origin. In these nontransformed cells, no effect of H‐1PV on viability or morphology of the cells was observed. In contrast, a lytic infection was induced in all neuroblastoma cell lines examined at MOIs between 0.001 and 10 pfu/cell. H‐1PV actively replicated with virus titres increasing up to 5,000‐fold within 48–96 hr after infection. The lytic effect of H‐1PV was observed independent of MYCN oncogene amplification or differentiation status. Moreover, a significant G2‐arrest and induction of apoptosis could be demonstrated. Infection efficiency, rapid virus replication and exhaustive lytic effects on neuroblastoma cells together with the low toxicity of H‐1PV for nontransformed cells, render this parvovirus a promising candidate for oncolytic virotherapy of neuroblastoma.
    Keywords: Neuroblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Apoptosis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 4
  • 5
    Language: English
    In: NUCLEIC ACIDS RESEARCH, 2013
    Description: 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.
    Keywords: Biology And Life Sciences ; Cell-Line ; Down-Regulation ; Microrna Expression ; Colorectal-Cancer ; Apoptosis ; Microarray ; Carcinoma ; Family ; Differentiation ; Histone Deacetylase Inhibitors
    ISSN: 0305-1048
    E-ISSN: 13624962
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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 2010, Vol.78(1), pp.237-245
    Description: Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation treatment (XRT) by altering numerous molecular pathways. We investigated the effect of pan-HDACIs such as suberoylanilide hydroxamic acid (SAHA) on radiation response in two osteosarcoma (OS) and two rhabdomyosarcoma (RMS) cell lines. Clonogenic survival, cell cycle analysis, and apoptosis were examined in OS (KHOS-24OS, SAOS2) and RMS (A-204, RD) cell lines treated with HDACI and HDACI plus XRT, respectively. Protein expression was investigated via immunoblot analysis, and cell cycle analysis and measurement of apoptosis were performed using flow cytometry. SAHA induced an inhibition of cell proliferation and clonogenic survival in OS and RMS cell lines and led to a significant radiosensitization of all tumor cell lines. Other HDACI such as M344 and valproate showed similar effects as investigated in one OS cell line. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In all investigated sarcoma cell lines, SAHA attenuated radiation-induced DNA repair protein expression (Rad51, Ku80). Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair, as well as increased apoptosis induction after exposure to HDACIs, can be mechanisms of radiosensitization by HDACIs.
    Keywords: Sarcoma ; Histone Deacetylase Inhibition ; Suberoylanilide Hydroxamic Acid (Saha) ; Radiosensitization ; Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 8
    Language: English
    In: The Journal of infectious diseases, 15 November 2004, Vol.190(10), pp.1758-61
    Description: Prevention of nasopharyngeal colonization may reduce the burden of pneumococcal infection during infancy. Colostrum obtained from Gambian mothers who had been vaccinated with either Pneumovax II or Mengivax A&C (n=8 per group) during pregnancy was examined for inhibition of adherence of Streptococcus pneumoniae serotypes 6B and 14 to pharyngeal epithelial cells in vitro. Pneumococcal adherence was significantly reduced in the presence of breast milk (P〈 or =.0001 for S. pneumoniae serotype 14; P=.036 for serotype 6B), independent of the concentration of secretory IgA antibodies. Maternal vaccination with polyvalent pneumococcal polysaccharide vaccine boosts the capacity of colostrum to inhibit adherence of pneumococci to pharyngeal epithelial cells. In breast-feeding populations, maternal vaccination might prevent pneumococcal disease in young infants.
    Keywords: Bacterial Adhesion ; Immunity, Maternally-Acquired ; Colostrum -- Immunology ; Epithelial Cells -- Microbiology ; Pharynx -- Microbiology ; Pneumococcal Infections -- Prevention & Control ; Pneumococcal Vaccines -- Immunology ; Streptococcus Pneumoniae -- Physiology
    ISSN: 0022-1899
    E-ISSN: 15376613
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  • 9
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2012.00600.x/abstract Byline: Till Milde(1)(2), Thomas Hielscher(3), Hendrik Witt(2)(4), Marcel Kool(4), Stephen C. Mack(5), Hedwig E. Deubzer(1)(2), Ina Oehme(1), Marco Lodrini(1), Axel Benner(3), Michael D. Taylor(5), Andreas von Deimling(6)(7), Andreas E. Kulozik(2), Stefan M. Pfister(2)(4), Olaf Witt(1)(*), Andrey Korshunov(6)(*) Keywords: ependymoma; nestin; risk stratification; WHO grade Abstract Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low-risk tumors, whereas grade III anaplastic ependymomas are considered high-risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin-positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression-free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co-regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics. Author Affiliation: (1)Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany (2)Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany (3)Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany (4)Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany (5)Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (6)Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (7)Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence: (*) Till Milde, MD, Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (E-mail: t.milde@dkfz.de). Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany Article Note: ([dagger]) Conflict of interest: The authors declare no conflict of interest. (*) These authors contributed equally to this work. Received 30 March 2012; Accepted 2 May 2012; Published Online Article Accepted 9 May 2012 Supporting information: Additional Supporting Information may be found in the online version of this article Figure S1. Nestin mRNA is differentially expressed in brain tumors and normal brain tissue. The database R2 was searched for nestin expression using publicly available datasets. Nestin is highly expressed in ependymoma (red) and astrocytomas and gliomas (astrocytoma, oligodendroglioma, anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma; blue), but not in medulloblastomas (blue). Normal adult tissue of varying brain regions (green) show low expression, while embryonal tissue shows high expression of nestin (green). Numbers following an underscore indicate the total numbers of samples in each dataset; in the second ependymoma dataset, letters following a83:a indicate the molecular subgroup; in the medulloblastoma, dataset letters following a120:a indicate the subgroup; in the embryogenesis, dataset numbers following a18:a indicate the week of human embryonic development; lca = large cell anaplastic; nd = not determined. Figure S2. Nestin protein is differentially expressed in ependymoma of differing location and grade. While no differences in nestin-positive and -negative ependymoma were found regarding gender or resection status, a significantly higher proportion of nestin-positive ependymoma was found in all supratentorial and WHO III ependymoma. When separated by age groups, a significantly higher proportion of pediatric supratentorial, and adult WHO III ependymoma were found to be nestin positive. infra = infratentorial; supra = supratentorial; STR = subtotal resection; GTR = gross total resection; nes = nestin; pos = positive; neg = negative; n.s. = not significant; *P 〈 0.05, **P 〈 0.005, ***P 〈 0.0001 (Fisher's exact t-test). Table S1. Cox proportional hazards model for progression-free (PFS) and overall survival (OS) estimation-univariable analysis. HR = hazard ration; CI = confidence interval. Table S2. Five-year progression-free (PFS) and overall survival (OS). infra = infratentorial; supra = supratentorial; neg = negative; pos = positive; infra = infratentorial; supra = supratentorial; PFA = posterior fossa group A; PFB = posterior fossa group B. Table S3. Genes co-regulated (correlation coefficient 〉0.5) with nestin from the Heidelberg dataset, ranked by correlation coefficient. Table S4. Genes significantly co-regulated (correlation coefficient 〉0.5) with nestin from the Toronto dataset, ranked by correlation coefficient. Table S5. Genes co-regulated with nestin found in both datasets (Heidelberg and Toronto), ranked by correlation coefficient for each dataset and displayed according to average rank. Table S6. Gene sets in the Heidelberg or Toronto dataset with significant adjusted P-value in both hypergeometric test and gene set enrichtment analysis (GSEA), with genes from the respective dataset (Supporting Table S3 or S4) in alphabetical order.
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: Brain Pathology, Nov, 2012, p.(1)
    Keywords: Gliomas -- Patient Outcomes ; Gliomas -- Analysis ; Universities And Colleges -- Analysis ; Adults -- Analysis ; Intermediate Filament Proteins -- Analysis ; Messenger Rna -- Analysis ; Stem Cell Research -- Analysis ; Transcription (Genetics) -- Analysis ; Children's Hospitals -- Analysis ; Cancer Research -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Anopheles -- Analysis ; Biometry -- Analysis ; Public Health -- Analysis ; Brain Tumors -- Patient Outcomes ; Brain Tumors -- Analysis
    ISSN: 1015-6305
    Source: Cengage Learning, Inc.
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