Disulfiram-Copper Synergies in Cancer Therapeutics

Disulfiram, a long-standing antialcoholism agent, has emerged as a versatile anticancer therapeutic when complexed with copper ions. The reaction between disulfiram and copper generates a copper diethyldithiocarbamate complex that exerts potent bioactivity by inducing reactive oxygen species, inhibiting the ubiquitin-proteasome system and triggering multiple programmed cell-death pathways, including apoptosis, endoplasmic reticulum stress and ferroptosis. These mechanisms converge to undermine tumour cell survival and to overcome resistance mechanisms mediated by pro-survival transducers such as NF-κB and Nrf2. Importantly, disulfiram–copper selectively targets cancer stem cells, which are implicated in metastasis, recurrence and chemoresistance, and acts synergistically with existing agents such as kinase inhibitors and platinum compounds. Preclinical studies in two- and three-dimensional culture systems, ex vivo tumour slices and in vivo xenografts have demonstrated broad activity across melanoma, pancreatic, nasopharyngeal and haematological malignancies. Ongoing efforts focus on optimising pharmacokinetics and stability through nanoparticle and delivery-matrix strategies to enable robust formation of the active copper complex within the tumour microenvironment.

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Disulfiram-Copper Synergies in Cancer Therapeutics publication trend

The graph below shows the total number of articles in disulfiram-copper synergies in cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Highly reactive molecules derived from oxygen that damage cellular components and can trigger programmed cell death.

Ferroptosis: Iron-dependent regulated cell death driven by lipid peroxidation, distinct from apoptosis and necrosis.

Endoplasmic reticulum (ER) stress: A cellular condition arising from accumulation of unfolded proteins in the ER that activates stress-response pathways and can lead to apoptosis.

Ubiquitin-proteasome system: The principal cellular machinery for targeted protein degradation, crucial for regulation of cell cycle, apoptosis and stress responses.

Cancer stem cells (CSCs): A subpopulation of tumour cells with self-renewal properties and intrinsic resistance to conventional therapies, central to metastasis and relapse.

References

1. Augmenting MEK inhibitor efficacy in BRAF wild-type melanoma: synergistic effects of disulfiram combination therapy. Journal of Experimental & Clinical Cancer Research (2024).
2. Hyperbaric Oxygen Boosts Antitumor Efficacy of Copper-Diethyldithiocarbamate Nanoparticles against Pancreatic Ductal Adenocarcinoma by Regulating Cancer Stem Cell Metabolism. Research (2024).
3. Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways. Cancers (2020).
4. On the interaction of copper( ii ) with disulfiram. Chemical Communications (2014).
5. The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells. Toxicology Research (2015).
6. Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2. Cell Death & Disease (2017).
7. Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents. Frontiers in Molecular Biosciences (2021).