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Clin Cancer Res. 2016 Aug 1;22(15):3860-75. doi: 10.1158/1078-0432.CCR-15-1798. Epub 2016 Mar 22.

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma.

Author information

1
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
2
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
3
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Drug Discovery Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
5
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada. Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
6
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Ontario, Canada.
7
Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
8
Department of Cell Biology & Anatomy, University of Calgary, Calgary, Alberta, Canada.
9
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. Department of Cell Biology & Anatomy, University of Calgary, Calgary, Alberta, Canada.
10
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
11
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Ontario, Canada.
12
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada. Department of Oncology, University of Calgary, Calgary, Alberta, Canada. senger@ucalgary.ca srobbins@ucalgary.ca.

Abstract

PURPOSE:

Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.

EXPERIMENTAL DESIGN:

To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.

RESULTS:

Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).

CONCLUSIONS:

DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 22(15); 3860-75. ©2016 AACR.

PMID:
27006494
DOI:
10.1158/1078-0432.CCR-15-1798
[Indexed for MEDLINE]
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