title: High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells.
abstract: Glioblastoma Multiforme (GBM) continues to have a poor patient prognosis despite optimal standard of care. Glioma stem cells (GSCs) have been implicated as the presumed cause of tumor recurrence and resistance to therapy. With this in mind, we screened a diverse chemical library of 2,000 compounds to identify therapeutic agents that inhibit GSC proliferation and therefore have the potential to extend patient survival. High-throughput screens (HTS) identified 78 compounds that repeatedly inhibited cellular proliferation, of which 47 are clinically approved for other indications and 31 are experimental drugs. Several compounds (such as digitoxin, deguelin, patulin and phenethyl caffeate) exhibited high cytotoxicity, with half maximal inhibitory concentrations (IC50) in the low nanomolar range. In particular, the FDA approved drug for the treatment of alcoholism, disulfiram (DSF), was significantly potent across multiple patient samples (IC50 of 31.1 nM). The activity of DSF was potentiated by copper (Cu), which markedly increased GSC death. DSF-Cu inhibited the chymotrypsin-like proteasomal activity in cultured GSCs, consistent with inactivation of the ubiquitin-proteasome pathway and the subsequent induction of tumor cell death. Given that DSF is a relatively non-toxic drug that can penetrate the blood-brain barrier, we suggest that DSF should be tested (as either a monotherapy or as an adjuvant) in pre-clinical models of human GBM. Data also support targeting of the ubiquitin-proteasome pathway as a therapeutic approach in the treatment of GBM.
authors.affiliation: The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA.
authors.forename: Parvinder
authors.initials: P
authors.lastname: Hothi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Martins
authors.forename: Liping
authors.initials: L
authors.lastname: Chen
authors.forename: Loic
authors.initials: L
authors.lastname: Deleyrolle
authors.forename: Jae-Geun
authors.initials: JG
authors.lastname: Yoon
authors.forename: Brent
authors.initials: B
authors.lastname: Reynolds
authors.forename: Greg
authors.initials: G
authors.lastname: Foltz
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000427:Alcohol Deterrents; D054852:Small Molecule Libraries; D004221:Disulfiram