2. Academic Validation
  3. Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen

Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen

  • Sci Rep. 2015 Feb 3;5:8202. doi: 10.1038/srep08202.
Martin Michaelis 1,  Bishr Agha 2,  Florian Rothweiler 2,  Nadine Löschmann 2,  Yvonne Voges 2,  Michel Mittelbronn 3,  Tatjana Starzetz 3,  Patrick N Harter 3,  Behnaz A Abhari 4,  Simone Fulda 4,  Frank Westermann 5,  Kristoffer Riecken 6,  Silvia Spek 7,  Klaus Langer 7,  Michael Wiese 8,  Wilhelm G Dirks 9,  Richard Zehner 10,  Jaroslav Cinatl 2,  Mark N Wass 11,  Jindrich Cinatl Jr 2
Affiliations

Affiliations

  • 1 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.
  • 2 Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
  • 3 Neurological Institute (Edinger Institute), Goethe University, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany.
  • 4 Institut für Experimentelle Tumorforschung in der Pädiatrie, Klinikum der Goethe-Universität, Komturstrasse 3a, 60528 Frankfurt am Main, Germany.
  • 5 Division Tumor Genetics, B030, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • 6 Forschungsabteilung Zell- und Gentherapie, Interdisziplinäre Klinik und Poliklinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 7 Institut für Pharmazeutische Technologie und Biopharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, 48149 Münster, Germany.
  • 8 Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 9 Leibniz-Institute Deutsche Sammlung für Mikroorganismen und Zellkulturen GmbH, Inhoffenstraße 7B, 38124 Braunschweig, Germany.
  • 10 Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Kennedyallee 104, 60596 Frankfurt am Main, Germany.
  • 11 Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
PMID: 25644037 DOI: 10.1038/srep08202
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.

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