title: Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide.
abstract: Glioblastomas (GBM) are associated with high rates of relapse. These brain tumors are often resistant to chemotherapies like temozolomide (TMZ) and there are very few treatment options available to patients. We recently reported that polo-like kinase-1 (PLK1) is associated with the proliferative subtype of GBM; which has the worst prognosis. In this study, we addressed the potential of repurposing disulfiram (DSF), a drug widely used to control alcoholism for the past six decades. DSF has good safety profiles and penetrates the blood-brain barrier. Here we report that DSF inhibited the growth of TMZ resistant GBM cells, (IC90=100 nM), but did not affect normal human astrocytes. At similar DSF concentrations, self-renewal was blocked by ~100% using neurosphere growth assays. Likewise the drug completely inhibited the self-renewal of the BT74 and GBM4 primary cell lines. Additionally, DSF suppressed growth and self-renewal of primary cells from two GBM tumors.These cells were resistant to TMZ, had unmethylated MGMT, and expressed high levels of PLK1. Consistent with its role in suppressing GBM growth, DSF inhibited the expression of PLK1 in GBM cells. Likewise, PLK1 inhibition with siRNA, or small molecules (BI-2536 or BI-6727) blocked growth of TMZ resistant cells. Our studies suggest that DSF has the potential to be repurposed for treatment of refractory GBM.
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC.
authors.forename: Joanna
authors.initials: J
authors.lastname: Triscott
authors.forename: Cathy
authors.initials: C
authors.lastname: Lee
authors.forename: Kaiji
authors.initials: K
authors.lastname: Hu
authors.forename: Abbas
authors.initials: A
authors.lastname: Fotovati
authors.forename: Rachel
authors.initials: R
authors.lastname: Berns
authors.forename: Mary
authors.initials: M
authors.lastname: Pambid
authors.forename: Margaret
authors.initials: M
authors.lastname: Luk
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kast
authors.forename: Esther
authors.initials: E
authors.lastname: Kong
authors.forename: Eric
authors.initials: E
authors.lastname: Toyota
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: Brian
authors.initials: B
authors.lastname: Toyota
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Dunn
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D000077204:Temozolomide
chemical_list: D000427:Alcohol Deterrents; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D004221:Disulfiram; D000077204:Temozolomide