Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide

被引:110
作者
Triscott, Joanna [1 ]
Lee, Cathy [1 ]
Hu, Kaiji [1 ]
Fotovati, Abbas [1 ]
Berns, Rachel [1 ]
Pambid, Mary [1 ]
Luk, Margaret [2 ]
Kast, Richard E. [3 ]
Kong, Esther [4 ]
Toyota, Eric [4 ]
Yip, Stephen [4 ]
Toyota, Brian [5 ]
Dunn, Sandra E. [1 ]
机构
[1] Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada
[2] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada
[3] Univ Vermont, Dept Psychiat, Burlington, VT USA
[4] BC Canc Agcy, Dept Pathol & Lab Med, Ctr Translat & Appl Genom, Vancouver, BC, Canada
[5] British Columbia Canc Agcy, Dept Surg, Vancouver, BC V5Z 4E6, Canada
关键词
glioblastoma; disulfiram; temozolomide; brain tumor; drug resistance; KINASE; 1; PLK1; NEURAL STEM-CELLS; KAPPA-B ACTIVITY; ALDEHYDE-DEHYDROGENASE; IN-VIVO; PROGNOSTIC BIOMARKER; INHIBITION; MULTIFORME; DIFFERENTIATION; PROLIFERATION;
D O I
10.18632/oncotarget.604
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 similar to 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.
引用
收藏
页码:1112 / 1123
页数:12
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