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.
Highlights
Cancer is a prominent cause of death worldwide which places an increasing burden on health and socioeconomic systems
Many recent studies have shown that there are other Cu-dependent or Cu-binding proteins such as mediator Of Cell Motility 1 (MEMO1), copper metabolism MURR1 domaincontaining protein 1 (COMMD1), Antioxidant Protein 1 (ATOX1) and secreted protein acidic and rich in cysteine (SPARC) which are involved in the process of cell migration and invasion by modulation of cytoskeleton, extracellular remodelling or by formation of adhesion sites (MacDonald et al, 2014; Nagaraju et al, 2014; Blockhuys et al, 2020)
The first approach involves using Cu chelators which reduce the bioavailability of Cu by directly binding to Cu; the second strategy is to use Cu ionophores that can increase the intracellular levels of Cu and exert antitumor effects through reactive oxygen species (ROS) production, proteasome inhibition, and apoptosis induction (Li, 2020)
Summary
Cancer is a prominent cause of death worldwide which places an increasing burden on health and socioeconomic systems. Platinum drugs are commonly used alone or in combination with other chemotherapeutic agents to treat various malignant diseases such as testicular, lung, breast, ovarian, colon, head and neck cancer (Ndagi et al, 2017; Rottenberg et al, 2021) Their use is still limited due to innate or acquired resistance in cancer cells and the undesirable side effects associated with their toxicity (Marine et al, 2020). Considering the reduction of development costs and affordability as a priority, repurposing old metal binding drugs to form complexes with Cu to selectively target cancer cells has been rigorously investigated in the past years (Bertolini et al, 2015; Saluja et al, 2018) One such candidate is Disulfiram (DSF), an old FDA approved anti-alcoholism drug with excellent metal chelation ability and demonstrated anticancer potential in a wide range of cancers in preclinical settings (Lu et al, 2021). We review the roles for Cu in cancer progression and the potential of harnessing copper homeostasis pathways in cancer cells with the Cu-binding activity of DSF and its derivatives, with a focus on recent developments in the translation of DSF for cancer therapy
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