The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells

Tawari, Patricia Erebi; Wang, Zhipeng; Najlah, Mohammad; Tsang, Chi Wai; Kannappan, Vinodh; Liu, Peng; McConville, Christopher; He, Bin; Armesilla, Angel L.; Wang, Weiguang

doi:10.1039/c5tx00210a

Cited by 86Bioactive Compounds and Antitumor AgentsMetal complexes synthesis and propertiesTrace Elements in Health

The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells

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Tawari, Patricia Erebi, Wang, Zhipeng, Najlah, Mohammad, Tsang, Chi Wai, Kannappan, Vinodh, Liu, Peng, McConville, Christopher, He, Bin +2 more·2015·Toxicology Research

DOI 10.1039/c5tx00210aPMC PMC5027600

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Abstract

The anticancer activity of disulfiram (DS) is copper(ii) (Cu)-dependent. This study investigated the anticancer mechanisms of DS/Cu using in vitro cytotoxicity and metabolic kinetic analysis. Our study indicates that DS/Cu targets cancer cells by the combination of two types of actions: (1) instant killing executed by DS/Cu reaction generated reactive oxygen species; (2) delayed cytotoxicity introduced by the end product, DDC-Cu. Nanoencapsulation of DS might shed light on repositioning of DS into cancer treatment.

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Disulfiram targets cancer cells in a copper-dependent manner through two complementary effects: instant short-term killing via ROS generated by the reaction of disulfiram and copper, and delayed, long-lasting cytotoxicity from the end product, Cu(DDC)2.
“DIS targets cancer cells in a copper-dependent manner through two complementary effects: (1) instant short-term killing via ROS generated by the reaction of DIS and copper, and (2) delayed, long-lasting cytotoxicity from the end product, Cu(DDC)2.54”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [54]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
The primary anticancer mechanism of action described was the generation of reactive oxygen species (ROS), which damage DNA, protein, and lipids, ultimately driving cells toward apoptosis.
“The primary anticancer mechanism of action described was the generation of reactive oxygen species (ROS), which damage DNA, protein, and lipids, ultimately driving cells toward apoptosis.54”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [54]
The Introduction says copper-triggered ROS can damage DNA, proteins and lipids and lead cells to apoptosis. But the Results and discussion and Conclusion describe two cytotoxic actions: an immediate, short-term ROS effect and a delayed, stronger effect of DDC-Cu. They do not establish ROS generation as the primary anticancer mechanism. Page numbers were not provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Given the extremely short half-lives of both disulfiram and DDC in circulation, no ROS and Cu(DDC)2 forms when oral disulfiram and copper are administered separately to patients-explaining the discrepancy between in vitro experiments and clinical outcomes.
“Given the extremely short half-lives of both DIS and DDC in circulation, no ROS and Cu(DDC)2 forms when oral DIS and copper are administered separately to patients—explaining the discrepancy between in vitro experiments and clinical outcomes.54”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [54]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Cu(DDC)2 is a stable compound with a serum half-life exceeding 4 h, and may follow the rule of conventional anticancer drugs, interfering with vital molecular pathways in cancer cells to induce apoptosis.
“In contrast with DIS, another of its metabolites, Cu(DDC)2 is a stable compound with a serum half-life exceeding 4 h, and may follow the rule of conventional anticancer drugs, interfering with vital molecular pathways in cancer cells to induce apoptosis.54”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [54]

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Authors: Tawari, P. E., Wang, Z., Najlah, M., Tsang, C. W., Kannappan, V., Liu, P., McConville, C., He, B., Armesilla, A. L., & Wang, W.
Affiliations: Research Institute in Healthcare Science, Faculty of Science & Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK. Fax: +44 (0)1902 322714; Tel: +44 (0)1902 322756
University of Wolverhampton (GB)
Anglia Ruskin University (GB)
University of Birmingham (GB)
Sichuan University (CN)
Corresponding author: Wang, Weiguang
ORCID: Wang, Zhipeng
Najlah, Mohammad
Kannappan, Vinodh
Liu, Peng
McConville, Christopher
He, Bin
Armesilla, Angel L.
Wang, Weiguang
Venue: Toxicology Research
Publisher: Oxford University Press (OUP)
Published: 2015-09-10
Volume: 4
Issue: 6
Pages: 1439-1442
ISSN: 2045-452X (ISSN-L)
2045-4538
DOI: 10.1039/c5tx00210a
PMC: PMC5027600
OpenAlex: W2112107833
Cited by: 86
References: 21
Citations by year: 2026: 2 · 2025: 5 · 2024: 12 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 9 · 2019: 14 · 2018: 6 · 2017: 4 · 2016: 3
FWCI: 3.42
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by/3.0/ (vor, 1541 d)
Locations: Toxicology Research (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Anglia Ruskin Research Online (Anglia Ruskin University) (submittedVersion)
Figshare (submittedVersion, cc-by)
Wolverhampton Intellectual Repository and E-Theses (University of Wolverhampton) (submittedVersion, cc-by)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords: disulfiram, copper(II), anticancer activity, cytotoxicity, reactive oxygen species, metabolic kinetics, drug repurposing, nanoencapsulation, cancer cells

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The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells

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