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

• Published in: Scientific reports 2015-02, Vol.5 (1), p.8202-8202, Article 8202
• Main Authors: Michaelis, Martin, Agha, Bishr, Rothweiler, Florian, Löschmann, Nadine, Voges, Yvonne, Mittelbronn, Michel, Starzetz, Tatjana, Harter, Patrick N., Abhari, Behnaz A., Fulda, Simone, Westermann, Frank, Riecken, Kristoffer, Spek, Silvia, Langer, Klaus, Wiese, Michael, Dirks, Wilhelm G., Zehner, Richard, Cinatl, Jaroslav, Wass, Mark N., Cinatl, Jindrich
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/2; 13/31; 13/89; 631/67/1059/2326; 631/67/70; 82/80; 96/109; 96/95; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; bcl-2-Associated X Protein - antagonists & inhibitors; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Cancer; Cell Line, Tumor; Chickens; Chorioallantoic membrane; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Drug resistance; GTP-binding protein; Humanities and Social Sciences; Humans; Imidazoles - antagonists & inhibitors; Imidazoles - metabolism; Leukemia; MDM2 protein; Mebendazole - analogs & derivatives; Mebendazole - pharmacology; multidisciplinary; Myeloma; Neuroblastoma; Neuroblastoma - metabolism; Neuroblastoma - pathology; p53 Protein; Piperazines - antagonists & inhibitors; Piperazines - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA Interference; RNA, Small Interfering - metabolism; RNA-mediated interference; Science; Signal Transduction - drug effects; siRNA; Therapeutic applications; Tubulin; Tumor cell lines; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08202

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.