Disulfiram';s Anticancer Activity: Evidence and Mechanisms

Abstract

Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence indicates that DSF possesses a great potential for the treatment of human cancers. DSF's anticancer activity has been demonstrated in both in vitro and in vivo model systems, and has been tested in human clinical trials for various cancer types. It is also evident that DSF can sensitize tumor cells to radiotherapy and enhance the cytotoxicity of anticancer drugs, thus DSF may serve as an adjuvant therapy. The key to DSF's anticancer action relates to its ability to suppress cancer stem cells by targeting aldehyde dehydrogenase (ALDH), a marker of cancer stem cells, and inhibit proteasome activity in cancer cells by forming complexes with metal ions. In addition, DSF targets epigenetic mechanisms and modulates cellular signaling pathways to slow down tumor progression. DSF also induces apoptosis, inhibits cancer cell proliferation, and suppresses cancer cell metastasis. Considering that the pharmacokinetics of DSF are well-established and a safety profile has been recorded, this compound is an attractive "old" drug that has great potential for rapid development into a new cancer therapeutic. This article provides a brief review of the history of DSF use in humans, evidence for its anticancer activities, the molecular mechanisms of DSF action that have been illustrated by recent studies, and the potential for repurposing DSF as a new chemotherapeutic drug in the near future.

Quantitative and Systems Pharmacology. 1.In SilicoPrediction of Drug–Target Interactions of Natural Products Enables New Targeted Cancer Therapy

“…64 In this study, disulfiram was predicted to have potential indications for 8 cancer types. Five of them are the new anticancer indications using Exp&ComNet only, including breast (Z=6.10, q <1 × 10 −5 ), colon (Z=6.51, q =0.0055), lung (Z=7.23, q <1 × 10 −5 ), thyroid (Z=7.23, q =0.0026), and uterine (Z=6.39, q=0.0179).…”

Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4

“…Due to the discovery that DSF and its metabolites kill cancer cells and slow tumor growth in animal models (3,4) and human patients (3,5), there has been an effort for repurposing this drug for cancer treatment (6–9). Several potential targets of DSF’s action, such as ALDH, NF-κB and proteasome, etc., were recently found (please see references therein) (10). It appears that DSF can act against a broad spectrum of malignancies, and, it can also target cancer cells with cancer stem cell-like properties.…”

“…It is previously documented that the DSF-copper complex is highly cytotoxic to cancer cells but not damage normal cells (10). The CuET enrichment in cancer cells may explain the selective cytotoxicity of DSF to cancer cells.…”

Human Endogenous Formaldehyde as an Anticancer Metabolite: Its Oxidation Downregulation May Be a Means of Improving Therapy

“…Since disulfiram effectively and irreversibly inhibits ALDH 1 and 2, its administration leads to the accumulation of acetaldehyde after alcohol intake, which causes redness of the skin (flash reaction), nausea, vomiting, and other unpleasant sensations, which causes the patient to be careful of alcohol intake. That is why for more than 80 years, disulfiram has been used as an agent for the treatment of alcoholism . However, special interest has been paid to the publication about the manifestation of the anticancer properties of disulfiram .…”

“…Indeed, disulfiram induces apoptosis in human cancer cells, including melanoma cells, breast cancer, pleural mesothelioma, pancreatic cancer cells, myeloid leukemia cells, glioblastoma, colorectal cancer cells, and cervical adenocarcinoma . Since the ALDH1 gene is a biomarker of CSCs, disulfiram has also been shown to play a key role in suppressing proliferation of these cells, which were obtained from brain, breast, ovarian, pancreatic, lung, liver, and blood tumors . This process may be accompanied by an increase in the formaldehyde content in the cells.…”