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

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.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…(In fact, on a molar basis copper (II) ions are probably the most potent known inhibitors of CBS, with an IC 50 of approximately 300 nM [ 167 , 174 , 175 ]). Disulfiram has been shown to exert anticancer effects in various preclinical models, and several targets have been proposed to explain this effect [ [176] , [177] , [178] , [179] ]. In fact, disulfiram (alone, or in various combinations, including a combination with copper) is currently in several clinical cancer trials [ [176] , [177] , [178] , [179] ].…”

“…Disulfiram has been shown to exert anticancer effects in various preclinical models, and several targets have been proposed to explain this effect [ [176] , [177] , [178] , [179] ]. In fact, disulfiram (alone, or in various combinations, including a combination with copper) is currently in several clinical cancer trials [ [176] , [177] , [178] , [179] ]. Thus, it is possible that disulfiram may be ultimately repurposed for cancer therapy, although the extent to which a CBS inhibitory effect contribute to its clinical anticancer action remains unclear.…”

Selective Targeting of Cancer Cells by Copper Ionophores: An Overview

“…DSF is an FDA-approved aldehyde dehydrogenase inhibitor for the treatment of alcoholism, and it has been effectively used for over 60 years. DSF, however, possesses other biological activities and there is been growing attention in repurposing DSF as an anticancer agent (Ekinci et al, 2019;Kannappan et al, 2021). This interest arises from the low cost, high availability, safety profile, and anticancer activity of DSF.…”

“…The mixture Cu-DSF has been tested as an adjuvant in combination with known chemotherapeutic drugs such as cisplatin, temozolomide, gemcitabine, doxorubicin, etc (Li H. et al, 2020). Mounting evidence has demonstrated that Cu-DSF can have several targets including ROS levels, the ubiquitinproteasome system (UPS), nuclear factor-kappa B (NF-κB), NPL4 (Chen et al, 2006;Skrott et al, 2017;Oliveri, 2020;Kannappan et al, 2021). Despite the excellent results of DSF in vitro and in vivo, clinical studies of DSF in patients with cancer were not successful.…”

“…This disappointing outcome could be related to the rapid degradation of DSF and its active metabolite or a different route of administration of DSF and Cu. The chemistry, pharmacokinetics, pharmacodynamics of DSF are comprehensively summarized by Kannappan et al (2021). So, here, only some aspects related to selectivity, are discussed.…”