Research: Complementary Reports:
Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide
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Joanna Triscott1, Cathy Lee1, Kaiji Hu1, Abbas Fotovati1, Rachel Berns1, Mary Pambid1, Margaret Luk2, Richard E. Kast3, Esther Kong4, Eric Toyota4, Stephen Yip4, Brian Toyota5 and Sandra E. Dunn1
1 Department of Pediatrics, University of British Columbia, Vancouver, BC
2 Department of Pathology, Vancouver General Hospital, Vancouver, BC
3 Department of Psychiatry, University of Vermont, Burlington, VT, USA
4 Department of Pathology & Laboratory Medicine, Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, BC
5 Department of Surgery, British Columbia Cancer Agency, Vancouver, BC
Sandra E. Dunn, email:
Keywords: glioblastoma, disulfiram, temozolomide, brain tumor, drug resistance
Received: September 27, 2012, Accepted: October 08, 2012, Published: October 08, 2012
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.
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