title: Anticancer effects of niclosamide in human glioblastoma.
abstract: OBJECTIVE
  Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need.
  
  
  METHODS
  Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo.
  
  
  RESULTS
  Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-κB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy.
  
  
  CONCLUSIONS
  Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application.
authors.affiliation: Stem Cell Pathologies, Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Wieland
authors.forename: Daniel
authors.initials: D
authors.lastname: Trageser
authors.forename: Sabine
authors.initials: S
authors.lastname: Gogolok
authors.forename: Roman
authors.initials: R
authors.lastname: Reinartz
authors.forename: Heike
authors.initials: H
authors.lastname: Höfer
authors.forename: Mihaela
authors.initials: M
authors.lastname: Keller
authors.forename: Anke
authors.initials: A
authors.lastname: Leinhaas
authors.forename: Ramona
authors.initials: R
authors.lastname: Schelle
authors.forename: Sabine
authors.initials: S
authors.lastname: Normann
authors.forename: Lil
authors.initials: L
authors.lastname: Klaas
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Yachnis
authors.forename: David W
authors.initials: DW
authors.lastname: Pincus
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Steindler
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Martin
authors.initials: M
authors.lastname: Glas
authors.forename: Björn
authors.initials: B
authors.lastname: Scheffler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009534:Niclosamide / Q000008:administration & dosage*; D051880:Receptors, Notch / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D051880:Receptors, Notch; D009534:Niclosamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases