title: Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen.
abstract: 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.
authors: 1] Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany [2] Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors: Martin
authors: M
authors: Michaelis
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Bishr
authors: B
authors: Agha
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Florian
authors: F
authors: Rothweiler
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Nadine
authors: N
authors: Löschmann
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Yvonne
authors: Y
authors: Voges
authors: Neurological Institute (Edinger Institute), Goethe University, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany.
authors: Michel
authors: M
authors: Mittelbronn
authors: Neurological Institute (Edinger Institute), Goethe University, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany.
authors: Tatjana
authors: T
authors: Starzetz
authors: Neurological Institute (Edinger Institute), Goethe University, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany.
authors: Patrick N
authors: PN
authors: Harter
authors: Institut für Experimentelle Tumorforschung in der Pädiatrie, Klinikum der Goethe-Universität, Komturstrasse 3a, 60528 Frankfurt am Main, Germany.
authors: Behnaz A
authors: BA
authors: Abhari
authors: Institut für Experimentelle Tumorforschung in der Pädiatrie, Klinikum der Goethe-Universität, Komturstrasse 3a, 60528 Frankfurt am Main, Germany.
authors: Simone
authors: S
authors: Fulda
authors: Division Tumor Genetics, B030, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Frank
authors: F
authors: Westermann
authors: Forschungsabteilung Zell- und Gentherapie, Interdisziplinäre Klinik und Poliklinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Kristoffer
authors: K
authors: Riecken
authors: Institut für Pharmazeutische Technologie und Biopharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, 48149 Münster, Germany.
authors: Silvia
authors: S
authors: Spek
authors: Institut für Pharmazeutische Technologie und Biopharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, 48149 Münster, Germany.
authors: Klaus
authors: K
authors: Langer
authors: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors: Michael
authors: M
authors: Wiese
authors: Leibniz-Institute Deutsche Sammlung für Mikroorganismen und Zellkulturen GmbH, Inhoffenstraße 7B, 38124 Braunschweig, Germany.
authors: Wilhelm G
authors: WG
authors: Dirks
authors: Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Kennedyallee 104, 60596 Frankfurt am Main, Germany.
authors: Richard
authors: R
authors: Zehner
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Jaroslav
authors: J
authors: Cinatl
authors: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors: Mark N
authors: MN
authors: Wass
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors: Jindrich
authors: J
authors: Cinatl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002645:Chickens; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C482205:nutlin 3; D008463:Mebendazole; D051736:Proto-Oncogene Proteins c-mdm2; C018945:flubendazole
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