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

Martin Michaelis, Bishr Agha, Florian Rothweiler, Nadine Löschmann, Yvonne Voges, Michel Mittelbronn, Tatjana Starzetz, Patrick N. Harter, Behnaz A. Abhari, Simone Fulda, Frank Westermann, Kristoffer Riecken, Silvia Spek, Klaus Langer, Michael Wiese, Wilhelm G. Dirks, Richard Zehner, Jaroslav Cinatl, Mark N. Wass, Jindrich Cinatl*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

55 Citations (Scopus)

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 IC 50 and IC 90 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.

Original languageEnglish
Article number8202
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 3 Feb 2015
Externally publishedYes

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