Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Vinodh Kannappan; Misha Ali; Benjamin Small; Gowtham Rajendran; Salena Elzhenni; Hamza Taj; Weiguang Wang; Q Ping Dou

doi:10.3389/fmolb.2021.741316

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Front Mol Biosci. 2021 Sep 17:8:741316. doi: 10.3389/fmolb.2021.741316. eCollection 2021.

Authors

Vinodh Kannappan^{1

2}, Misha Ali^{3

4}, Benjamin Small¹, Gowtham Rajendran¹, Salena Elzhenni³, Hamza Taj³, Weiguang Wang^{1

2}, Q Ping Dou³

Affiliations

¹ Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom.
² Disulfican Ltd, University of Wolverhampton Science Park, Wolverhampton, United Kingdom.
³ Departments of Oncology, Pharmacology and Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.
⁴ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

Abstract

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)₂ also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)₂ at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)₂ complex into cancer therapeutics.

Keywords: cancer; cancer stem cells; copper; diethyldithiocarbamate; disulfiram; disulfiram copper complex; drug repurposing; drug-delivery-system.

Publication types

Review