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

Michaelis, Martin and Agha, Bishr and Rothweiler, Florian and Löschmann, Nadine and Voges, Yvonne and Mittelbronn, Michel and Starzetz, Tatjana and Harter, Patrick N and Abhari, Behnaz A and Fulda, Simone and Westermann, Frank and Riecken, Kristoffer and Spek, Silvia and Langer, Klaus and Wiese, Michael and Dirks, Wilhelm G and Zehner, Richard and Cinatl, Jaroslav and Wass, Mark N. and Cinatl, Jindrich (2015) Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen. Scientific reports, 5 (-). p. 8202. ISSN 2045-2322. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://www.nature.com/srep/2015/150203/srep08202/f...

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.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 08 Mar 2015 16:28 UTC
Last Modified: 06 Jun 2017 11:17 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/47585 (The current URI for this page, for reference purposes)
ORCiD (Michaelis, Martin): http://orcid.org/0000-0002-5710-5888
ORCiD (Wass, Mark N.): http://orcid.org/0000-0001-5428-6479
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