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. 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

Xueqing Lun  1 , J Connor Wells  2 , Natalie Grinshtein  3 , Jennifer C King  1 , Xiaoguang Hao  1 , Ngoc-Ha Dang  1 , Xiuling Wang  1 , Ahmed Aman  4 , David Uehling  4 , Alessandro Datti  5 , Jeffrey L Wrana  6 , Jacob C Easaw  7 , Artee Luchman  8 , Samuel Weiss  9 , J Gregory Cairncross  10 , David R Kaplan  11 , Stephen M Robbins  12 , Donna L Senger  12
Affiliations

VSports注册入口 - Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Xueqing Lun et al. Clin Cancer Res. .

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. VSports手机版.

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. V体育安卓版.

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 V体育ios版. 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 VSports最新版本. Clin Cancer Res; 22(15); 3860-75. ©2016 AACR. .

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