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

Lun, Xueqing; Wells, J.C.; Grinshtein, Natalie; King, Jennifer C.; Hao, Xiaoguang; Dang, Ngoc-Ha; Wang, Xuiling; Aman, Ahmed; Uehling, David; Datti, Alessandro; Wrana, Jeffrey L.; Easaw, Jacob C.; Luchman, Artee; Weiss, Samuel; Cairncross, J. Gregory; Kaplan, David R.; Robbins, Stephen M.; Senger, Donna L.

doi:10.1158/1078-0432.ccr-15-1798

Cited by 155 publications

(124 citation statements)

References 51 publications

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“…3, 33 As noted in the supplementary data ( Figure S1), the in vitro activity of Cu(DDC) 2 against U251 MG and F98 cell lines was comparable to that observed for the MV-4-11 cells (Figure 1). The 72-h IC 50 of Cu(DDC) 2 was 384 and 417 nM for U251 MG cells and F98 cells, respectively.…”

supporting

confidence: 69%

“…Interestingly, DSF and copper have been reported to be effective against brain tumor-initiating cells (BTICs) that are senescent. 3,33,38 Thus, the ability of Cu(DDC) 2 to be effective regardless of cell-cycle stage may contribute to the drug's ability to kill BTICs. Our in vitro studies (Figure 2) indicate that the activity of Cu(DDC) 2 is not mediated by the generation of ROS, that is, no increase in ROS production was observed when cells were incubated with Cu(DDC) 2 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, Lun et al have demonstrated that temozolomide (TMZ) can be used in combination with DSF and copper. 33 It would be a natural transition to examine if Cu(DDC) 2 could be used in combination with TMZ. Also, given a mechanism that involves proteosome inhibition, Cu(DDC) 2 may be useful when combined with other drugs known to enhance the activity of known proteasome inhibitors such as bortezomib.…”

Section: Discussionmentioning

confidence: 99%

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Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Wehbe¹,

Anantha²,

Shi³

et al. 2017

IJN

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Copper diethyldithiocarbamate (Cu(DDC) 2 ) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC) 2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC) 2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC) 2 formulation prepared through a method that involves synthesis of Cu(DDC) 2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC) 2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4–11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC) 2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC) 2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC) 2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC (0−∞) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC) 2 formulation was subsequently evaluated in the MV-4–11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC) 2 formulation in vivo.

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supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Wehbe¹,

Anantha²,

Shi³

et al. 2017

IJN

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“…1E and data not shown). We also evaluated CSPα levels in conditioned media from human brain tumors of 11 distinct origins 44, 45 . Out of 11 brain tumor initiating cells examined, 9 were found to secrete CSPα.…”

Section: Resultsmentioning

confidence: 99%

“…Surgical samples from patients with newly diagnosed or recurrent glioblastoma were obtained from the Tumor Tissue Bank within the Arnie Charbonneau Cancer Institute, transported to the BTIC Core Facility (Calgary, Alberta) and established as described previously 44, 45 . This study has Institutional review board approval under the “Brain Tumor and Related Tissue Bank protocol-V2” and approved by Foothills Hospital and the Conjoint Health Research Ethics Board and all methods were performed in accordance with the relevant guidelines and regulations.…”

Section: Methodsmentioning

confidence: 99%

Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo

Deng

Koutras

Donnelier

et al. 2017

Sci Rep

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The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα. Extracellular vesicles (EV’s) have been implicated in a wide range of functions. However, the functional significance of neural EV’s remains to be established. Here we demonstrate that co-expression of CSPα with the disease-associated proteins, polyglutamine expanded protein 72Q huntingtinex°n1 or superoxide dismutase-1 (SOD-1G93A) leads to the cellular export of both 72Q huntingtinex°n1 and SOD-1G93A via EV’s. In contrast, the inactive CSPαHPD-AAA mutant does not facilitate elimination of misfolded proteins. Furthermore, CSPα-mediated export of 72Q huntingtinex°n1 is reduced by the polyphenol, resveratrol. Our results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSPα thus represents a potential therapeutic target for neurodegenerative diseases.

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Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

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

Cited by 155 publications

References 51 publications

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

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