Repurposing drugs approved for other applications is a promising approach to finding new treatments for cancer. One example is disulfiram (DSF; Antabuse), which has been used for decades as an alcohol aversion therapy. Now, researchers are studying disulfiram as a possible new treatment for cancer.
Disulfiram has been shown to have antineoplastic effects, including inhibition of tumor growth, angiogenesis, invasion, and metastasis. Researchers of two epidemiologic studies have used the Danish health registry to assess the protective effect of DSF against cancer. In a population-based case-control study, Askgaard and colleagues found that DSF reduced the risk of prostate and breast cancer.1 In the second study, Skrott et al reported that patients who continued to use DSF after a cancer diagnosis had a lower risk of death from cancer compared with subjects who discontinued the drug at diagnosis.2
Although the detailed mechanism of DSF cytotoxicity is not fully understood, it is thought to be related to the formation of metabolite-copper complexes within cells. The copper-dependent anticancer activity of DSF makes it a promising candidate because many tumors have a copper concentration two to three times higher than normal tissues.
Researchers from the University of South Carolina College of Pharmacy’s Department of Drug Discovery and Biomedical Sciences, Columbia, SC, recently sought to repurpose DSF by using diethyldithiocarbamate (DDTC), the therapeutically active metabolite of DSF, to develop a polymer conjugate nanoparticle for targeted cancer delivery.
Huacheng He led the investigation, and results were published in Acta Biomaterialia.
He and colleagues found that the nanoparticle enters cancer cells through β-D-galactose receptor-mediated endocytosis. Upon cellular uptake, the nanoparticle degrades and releases DDTC in a response to the high intracellular level of glutathione (GSH). The DDTC subsequently forms a complex with copper and kills a broad spectrum of cancer cells without affecting normal cells.
The researchers replicated metastatic ovarian cancer tumors by intraperitoneally injecting cells from the human ovary cancer cell line (SKOV-3) into nude female mice. After 2 weeks of tumor growth, the mice were randomized to phosphate-buffered saline (PBS) or one of five agents and treated weekly for 3 weeks. The treatments were:
- DSF plus copper ions (DSF/Cu)
- DSF nanoparticle plus copper ions (DNP/Cu)
- Loaded DSF nanoparticle (LDNP)
- Loaded DSF nanoparticle plus copper ions (LDNP/Cu). LDNP is DSF nanoparticle with lactobionic acid, a selective ligand for D-galactose receptor that is effective in targeting cancer cells.
After monitoring tumor growth weekly, He and colleagues found that LDNP/Cu was the most effective in impeding tumor growth, and that rapid tumor growth occurred in controls.
In addition, the researchers observed numerous tumors in the abdominal cavities of controls and mice treated with DSF/Cu, but fewer in mice treated with nanoparticles.
Researchers evaluated the systemic toxicity of the nanoparticles, in part, via histologic exam of the liver, and found no noticeable differences between the treatment groups.
“Altogether, the in vivo data indicate that the LDNP/Cu nanoparticle could be an effective and safe tool for the treatment of advanced ovarian cancer,” the authors concluded.
- Askgaard G, et al. Eur J Cancer Prev. 2014;23(3):225-232.
- Skrott Z, et al. 2017;552(7684):194-199.