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  • Neuroblastoma
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  • 1
    In: Molecular BioSystems, 2011, Vol.7(1), pp.200-214
    Description: Chemotherapy of cancer experiences a number of shortcomings including development of drug resistance. This fact also holds true for neuroblastoma utilizing chemotherapeutics as vincristine. We performed a comparative analysis of molecular and cellular mechanisms associated with vincristine resistance utilizing cell line as well as human tissue data. Differential gene expression analysis revealed molecular features, processes and pathways afflicted with drug resistance mechanisms in general, and specifically with vincristine significantly involving actin associated features. However, specific mode of resistance as well as underlying genotype of parental, vincristine sensitive cells apparently exhibited significant heterogeneity. No consensus profile for vincristine resistance could be derived, but resistance-associated changes on the level of individual neuroblastoma cell lines as well as individual patient profiles became clearly evident. Based on these prerequisites we utilized the concept of synthetic lethality aimed at identifying hub proteins which when inhibited promise to induce cell death due to a synthetic lethal interaction with down-regulated, chemoresistance associated features. Our screening procedure identified synthetic lethal hub proteins afflicted with actin associated processes holding synthetic lethal interactions to down-regulated features individually found in all chemoresistant cell lines tested, therefore promising an improved therapeutic window. Verification of such synthetic lethal hub candidates in human neuroblastoma tissue expression profiles indicated the feasibility of this screening approach for addressing vincristine resistance in neuroblastoma.
    Keywords: Antineoplastic Agents -- Pharmacology ; Drug Resistance, Neoplasm -- Physiology ; Neoplasm Proteins -- Metabolism ; Neuroblastoma -- Metabolism ; Vincristine -- Pharmacology;
    ISSN: 1742-206X
    E-ISSN: 1742-2051
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  • 2
    Language: English
    In: Biochemical Pharmacology, 2010, Vol.79(2), pp.130-136
    Description: Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate-induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3(r)CDDP(1000) showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NC160 cell line panel clearly separated UKF-NB-3(r)CDDP(1000) from the other cell lines. L-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3(r)CDDP(1000) cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells. (C) 2009 Elsevier Inc. All rights reserved.
    Keywords: Neuroblastoma ; Artesunate ; Artemisinin ; Chemoresistance ; Cancer ; Chemotherapy ; Gamma-Glutamylcysteine Synthetase ; Traditional Chinese Medicine ; Amino-Acid-Sequence ; Ascites Tumor-Cells ; Cytotoxic Action ; Multidrug-Resistance ; Expression Profiles ; Falciparum-Malaria ; Oxidative Stress ; Leukemia-Cells
    ISSN: 0006-2952
    E-ISSN: 18732968
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  • 3
    Language: English
    In: PLoS ONE, Sept 30, 2014, Vol.9(9)
    Description: Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
    Keywords: Tumor Proteins ; Apoptosis ; Phosphotransferases ; Neuroblastoma
    ISSN: 1932-6203
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  • 4
    Language: English
    In: Intervirology, 1996, Vol.39(4), pp.259-269
    Description: Although there is no definitive evidence of the association of human cytomegalovirus (HCMV) infection with human cancers, the oncogenic potential of HCMV has been well established by in vitro studies demonstrating the ability of UV-irradiated or infectious virus to transform a variety of cells. After prolonged passaging the transformed cell type was maintained while HCMV DNA sequences were no more detectable. Three morphological transforming regions (mtr) of HCMV have been identified. The effects of HCMV on cellular functions which may be associated with the malignant phenotype include the expression of oncogenes and transcriptional activation of growth factors and interleukin synthesis. In infected cells, HCMV induces cytoskeletal alterations and changes in expression of cell surface receptors for extracellular matrix proteins which could result in increased motility and dissemination of cancer cells. Several human neuroblastoma cell lines undergo maturation in different neural crest derived cell types upon treatment with oncogenic potential agents, i. e. retinoic acid. The persistent HCMV infection of neuroblastoma cells (〉1 year) is accompanied by the increased expression of oncoproteins (i.e. N-myc) and decreased expression of tyrosine hydroxylase and dopamine-β-hydroxylase. The activation of the cellular metabolism is due to HCMV binding to cellular receptors (prior to virus gene expression) and to the activity of HCMV immediate early (IE) gene products. IE proteins act directly as transcriptional activators or their activity is mediated by a variety of cellular transcription factors. HCMV infection may result in activation of promoters of cellular genes coding for cytokines, replication enzymes, protooncogenes and viral promoters. Recently it has been demonstrated that HCMV IE proteins block apoptosis probably by suppressing the ability of the antioncogene p53 to activate a reporter gene. The interactions of HCMV with tumor suppressor proteins such as p53 or retinoblastoma (pRb) susceptibility protein are reminiscent of those mediated by the oncoproteins of DNA tumor viruses. The acquisition of a fully malignant phenotype by normal cells is thought to require several mutations in a number of cellular genes. In this connection, HCMV may play the role of a nonobligate either direct or indirect cofactor for tumor genesis, e.g. by blocking apoptosis, which may be an essential requirement for tumor progression. Due to the stimulation of growth factors and/or inhibition of antioncogenes by its gene products, HCMV may modulate the malignant potential of tumor cells.
    Keywords: Original Paper ; Cytomegalovirus, Human ; Neuroblastoma ; Oncogenic Potential ; Differentiation ; Biology
    ISSN: 0300-5526
    E-ISSN: 1423-0100
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  • 5
    Language: English
    In: Molecular Cancer, 2009, Vol.8(1), pp.urn:issn:1476-4598
    Description: Background: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated...
    Keywords: Endothelial Growth-Factor ; In-Vivo ; Melanoma-Cells ; Tumor-Growth ; N-Myc ; Extracellular-Matrix ; Angiogenic Factors ; Cytokine Network ; Vegf Expression ; Blood-Vessels
    ISSN: 1476-4598
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  • 6
    Language: English
    In: Cell Communication & Adhesion, 01 January 2002, Vol.9(3), pp.131-147
    Description: The precise function of cell adhesion molecules in the hematogenous phase of neuroblastoma metastasis is poorly understood. The aim of this study was to investigate whether neural cell adhesion molecule (NCAM) modulates neuroblastoma cell (NB) adhesion and transendothelial penetration in a...
    Keywords: Ncam ; Neuroblastoma ; Adhesion ; Biology
    ISSN: 1541-9061
    E-ISSN: 1543-5180
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  • 7
    Language: English
    In: Medical microbiology and immunology, 2011, Vol.200(1), pp.1-5
    Description: The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence. ; Includes references ; p. 1-5.
    Keywords: Neoplasms ; Cytomegalovirus ; Glioblastoma ; Tumour Virus ; Neuroblastoma ; Oncomodulation
    ISSN: 0300-8584
    E-ISSN: 14321831
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  • 8
    Language: English
    In: Cancer Letters, Sept 10, 2017, Vol.403, p.74
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.canlet.2017.05.027 Byline: Madhu Kollareddy (a), Alice Sherrard (b), Ji Hyun Park (a), Marianna Szemes (a), Kelli Gallacher (a), Zsombor Melegh (a), Sebastian Oltean (c), Martin Michaelis (d), Jindrich Cinatl Jr. (e), Abderrahmane Kaidi (b), Karim Malik [K.T.A.Malik@bristol.ac.uk] (a,*) Keywords Neuroblastoma; Chemotherapy; YK-4-279; Mitosis; Drug resistance/synergy Highlights * The small molecule inhibitor YK-4-279 can trigger p53-independent apoptosis in neuroblastoma cell lines. * YK-4-279 induces mitotic arrest with multipolar, fragmented and unseparated spindles. * YK-4-279 acts differently from paclitaxel and vincristine. * YK-4-279 can overcome resistance to vincristine and synergize with other inhibitors of mitosis. Abstract Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers. Abbreviations ALK, Anaplastic Lymphoma kinase; EGF, Epidermal growth factor; ERK, extracellular signal-regulated kinases; GFP, green fluorescent protein; kDa, kilodaltons; MAPK, mitogen-activated protein kinase; MEK, Mitogen-activated protein kinase kinase; MTT, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide; PBS, Phosphate-buffered saline; pHH3, phospho-histone H3 (ser10); RNase A, ribonuclease A; QVD, quinolyl-valyl-O-methylaspartyl-(-2,6-difluorophenoxy)- methyl ketone; SDS-PAGE, sodium-dodecyl sulphate-polyacrylamide gel electrophoresis; TERT, Telomerase reverse transcriptase Author Affiliation: (a) Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK (b) Nuclear Dynamics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK (c) School of Physiology and Pharmacology, University of Bristol, Bristol, UK (d) Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK (e) Institut fAaAaAeA r Medizinische Virologie, Klinikum der Goethe-UniversitAaAa Frankfurt am Main, Germany * Corresponding author. Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, Biomedical Sciences Building, University Walk, University of Bristol, Bristol, BS8 1TD, UK. Article History: Received 29 March 2017; Revised 24 May 2017; Accepted 26 May 2017
    Keywords: Drug Resistance – Development and Progression ; Drug Resistance – Analysis ; Lymphomas – Development and Progression ; Lymphomas – Analysis ; Mitogens – Analysis ; Neuroblastoma – Development and Progression ; Neuroblastoma – Analysis ; Tumor Proteins – Development and Progression ; Tumor Proteins – Analysis ; Cell Death – Analysis ; Chemotherapy – Analysis
    ISSN: 0304-3835
    E-ISSN: 18727980
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  • 9
    In: Scientific Reports, 2015, Vol.5
    Description: Flubendazole was shown to exert anti-leukaemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was tested for its effects on the viability of in total 461 cancer cell lines. Neuroblastoma was identified as highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities. Flubendazole also reduced the viability of five primary neuroblastoma samples in nanomolar concentrations thought to be achievable in humans and inhibited vessel formation and neuroblastoma tumour growth in the chick chorioallantoic membrane assay. Resistance acquisition is a major problem in high-risk neuroblastoma. 119 cell lines from a panel of 140 neuroblastoma cell lines with acquired resistance to various anti-cancer drugs were sensitive to flubendazole in nanomolar concentrations. Tubulin-binding agent-resistant cell lines displayed the highest flubendazole IC50 and IC90 values but differences between drug classes did not reach statistical significance. Flubendazole induced p53-mediated apoptosis. The siRNA-mediated depletion of the p53 targets p21, BAX, or PUMA reduced the neuroblastoma cell sensitivity to flubendazole with PUMA depletion resulting in the most pronounced effects. The MDM2 inhibitor and p53 activator nutlin-3 increased flubendazole efficacy while RNAi-mediated p53-depletion reduced its activity. In conclusion, flubendazole represents a potential treatment option for neuroblastoma including therapy-refractory cells.
    Keywords: Biology;
    ISSN: 20452322
    E-ISSN: 20452322
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  • 10
    Language: English
    In: Molecular Cancer, Sept 29, 2009, Vol.8, p.80
    Description: Background Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. Conclusion A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target.
    Keywords: Drug Resistance -- Health Aspects ; Drug Resistance -- Genetic Aspects ; Drug Resistance -- Research ; Gene Expression -- Research ; Neuroblastoma -- Genetic Aspects ; Neuroblastoma -- Development And Progression ; Neuroblastoma -- Drug Therapy ; Neuroblastoma -- Research ; Computational Biology -- Usage
    ISSN: 1476-4598
    Source: Cengage Learning, Inc.
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