Abstract
Simple SummaryIn recent years, disulfiram has gained in attention as an anticancer drug due to its broad activity against various cancers, and its mechanisms and molecular targets have been deciphered in vitro and in vivo. One of these cancers is melanoma. Initial data from human studies show some benefit, but do not confirm its broad efficacy as a monotherapy. However, combination approaches could pave the way for exploiting the beneficial effects of disulfiram for cancer patients, including those with melanoma. New therapeutic concepts such as anti-PD-1-based immunotherapy or targeted therapy with BRAF and MEK inhibitors have significantly improved the survival of melanoma patients. However, about 20% of patients with targeted therapy and up to 50% with immunotherapies do not respond to their first-line treatment or rapidly develop resistance. In addition, there is no approved targeted therapy for certain subgroups, namely BRAF wild-type melanomas, although they often bear aggressive tumor biology. A repurposing of already approved drugs is a promising strategy to fill this gap, as it will result in comparatively low costs, lower risks and time savings. Disulfiram (DSF), the first drug to treat alcoholism, which received approval from the US Food and Drug Administration more than 60 years ago, is such a drug candidate. There is growing evidence that DSF has great potential for the treatment of various human cancers, including melanoma. Several mechanisms of its antitumor activity have been identified, amongst them the inhibition of the ubiquitin-proteasome system, the induction of reactive oxygen species and various death signaling pathways. This article provides an overview of the application of DSF in humans, its molecular mechanisms and targets in cancer therapy with a focus on melanoma. The results of clinical studies and experimental combination approaches of DSF with various cancer therapies are discussed, with the aim of exploring the potential of DSF in melanoma therapy.
Highlights
Cluster of Excellence iFIT (EXC 2180) Image Guided and Functionally Instructed Tumor Therapies, University Hospital Tübingen, 72076 Tübingen, Germany
DSF mediated in vitro cytotoxicity was rather specific for melanoma cell lines, as these were more affected by disulfiram than melanocytes and other benign cells [18,23]
The results indicated a protective effect of DSF against prostate and breast cancer, but not against melanoma [15]
Summary
Disulfiram (DSF) was first synthesized as a novel composite from thiocarbamide (thiourea) in 1881 by the German chemist M. In 1937, E.E. Williams reported for the first time on the alcohol intolerance of workers who were exposed to DSF during the vulcanization of rubber and consumed alcohol [3]. A vermifuge effect was shown in rabbits Based on these results, it was decided to test DSF against verminal infections in humans. The interactions proved to be dose-dependent in patients using up to 3000 mg of DSF per day [5]. With this knowledge about the alcohol-intolerance-mediating property of DSF, Ruth Fox began administering DSF to treat alcohol addiction in the United States in 1949. 8.6 g/kg, Antabuse® is very safe and has been used for the management of alcohol dependency for the last 60 years [4,6,7,8,9]
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