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

被引：67

作者：

Michaelis, Martin ^{[1
,2
,3
]}

Agha, Bishr ^{[1
]}

Rothweiler, Florian ^{[1
]}

Loeschmann, Nadine ^{[1
]}

Voges, Yvonne ^{[1
]}

Mittelbronn, Michel ^{[4
]}

Starzetz, Tatjana ^{[4
]}

Harter, Patrick N. ^{[4
]}

Abhari, Behnaz A. ^{[5
]}

Fulda, Simone ^{[5
]}

Westermann, Frank ^{[6
]}

Riecken, Kristoffer ^{[7
]}

Spek, Silvia ^{[8
]}

Langer, Klaus ^{[8
]}

Wiese, Michael ^{[9
]}

Dirks, Wilhelm G. ^{[10
]}

Zehner, Richard ^{[11
]}

Cinatl, Jaroslav ^{[1
]}

Wass, Mark N. ^{[2
,3
]}

Cinatl, Jindrich, Jr. ^{[1
]}

机构：

[1] Univ Frankfurt Klinikum, Inst Med Virol, D-60596 Frankfurt, Germany

[2] Univ Kent, Ctr Mol Proc, Canterbury CT2 7NJ, Kent, England

[3] Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England

[4] Goethe Univ Frankfurt, Edinger Inst, Neurol Inst, D-60528 Frankfurt, Germany

[5] Univ Frankfurt Klinikum, Inst Expt Tumorforsch Padiatrie, D-60528 Frankfurt, Germany

[6] German Canc Res Ctr, Div Tumor Genet, D-69120 Heidelberg, Germany

[7] Univ Klinikum Hamburg Eppendorf, Interdisziplinare Klin & Poliklin Stammzelltransp, Forsch Abt Zell & Gentherapie, D-20246 Hamburg, Germany

[8] Univ Munster, Inst Pharmazeut Technol & Biopharm, D-48149 Munster, Germany

[9] Univ Bonn, Inst Pharmaceut, D-53121 Bonn, Germany

[10] Leibniz Inst Deutsch Sammlung Mikroorganismen & Z, D-38124 Braunschweig, Germany

[11] Univ Frankfurt Klinikum, Inst Rechts Med, D-60596 Frankfurt, Germany

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

关键词：

ANTHELMINTIC DRUG MEBENDAZOLE; ONTOLOGY LEGO VECTORS; MULTIDRUG-RESISTANCE; CANCER-CELLS; P53; PATHWAY; ALBENDAZOLE; TUBULIN; INACTIVATION; INHIBITOR; APOPTOSIS;

D O I：

10.1038/srep08202

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

共 47 条

[1] Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme [J].