Cancer is a prominent cause of death worldwide which places an increasing burden on health and socioeconomic systems. According to the estimates provided by World Health Organization (WHO) in 2019, cancer is already the first or second cause of death before the age of 70 in 112 of 183 countries and its prevalence is expected to increase (Sung et al., 2021). It is predicted that ageing combined with population growth will result in an increase in the annual number of new cancer cases from 18.1 million in 2018 to 28.4 million in 2040. This increase will be severe in low- and middle-income countries, which are least prepared to the challenge (Wild, 2019; Sung et al., 2021).

In addition to surgery and radiation, chemotherapy which uses broad-spectrum cytotoxic drugs that do not differentiate cancer cells from normal cells, remains as the main arm of cancer treatment, despite its toxicity and significant side effects (Bedard et al., 2020). The discovery of potent metal-based chemotherapeutic drugs such as cisplatin, oxaliplatin and carboplatin paved the way for the development of a new class of inorganic metal-based chemotherapeutic agents (Rottenberg et al., 2021). These metal drugs bind to DNA and block the transcription and replication that initiate the process of apoptosis in cancer cells. 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). However, 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).

By the turn of the millennium, insights into the genomic landscapes of cancers led to the development of drugs that selectively target cancer cells while sparing normal cells, hence having high potency and fewer adverse effects (Druker et al., 2001; Cohen et al., 2021). Over the past two decades, over 40 receptor tyrosine kinase inhibitors (TKIs) have been approved by the US FDA as targeted drugs for cancer treatment (Cohen et al., 2021). Although TKIs such as imatinib have shown promising outcomes in some cancers like chronic myeloid leukaemia, the problems associated with emergence of resistance to treatment, tumour relapse and undesirable side effects and toxicity, remain as the major challenges for their use in cancer patients (Kobayashi et al., 2005; Marine et al., 2020). More recently, it has been identified that even the state-of-the-art immunotherapies, such as immune check-point inhibitors and adoptive T cell therapies which revolutionised the treatment of advanced cancers, are no exception to innate and acquired resistance mechanisms in cancers (Restifo et al., 2016; Hiam-Galvez et al., 2021). Moreover, the current growth in the cost of many targeted therapies for cancer discourages their use in clinical setting in terms of cost benefit ratio evaluation by healthcare agencies (Saluja et al., 2018; Leighl et al., 2021).

Owing to the clinical success of platinum drugs in a wide range of cancers and the requirement for reduction of treatment costs, there has been renewed interest in the development of novel metallodrugs in the field of inorganic drug development (Ndagi et al., 2017; Rottenberg et al., 2021). While the question of how cancer cells develop resistance to various targeted therapies still remains, there has been better understanding of the fundamental roles that several metal ions play in biological processes and their interaction with biomolecules. Recently, several non-platinum metallodrugs such as copper(II) (Cu), gold(I)-, ruthenium(III), gallium(III), cobalt(II)- and nickel(II)-based compounds have been investigated for their anticancer potential (Frezza et al., 2010; Chitambar, 2012; Lee et al., 2020; Yusoh et al., 2020). Each transition metal has unique ligand exchange kinetics and redox potentials and hence the choice of the metal centre and ligand design play a crucial role in the therapeutic effects of the metallo-complex compounds. Among transition metals, Cu has been widely proven to be used in development of therapeutic compounds due to the interesting anticancer properties and ease of handling to reduce side effects (Shanbhag et al., 2021). The nature of Cu ligands and the planar square geometry exhibited by Cu complexes is ideal for causing DNA specific damage very similar to that of platinum compounds (Lelievre et al., 2020). Cu plays crucial roles in many biological processes such as free radical detoxification, mitogenic signalling, immunomodulation, peptide processing, cellular respiration, and proliferation, and hence it is an indispensable micronutrient for all living organisms (Michniewicz et al., 2021; Shanbhag et al., 2021). However, in pathological conditions like cancer, excessive levels of Cu have been associated with enhanced proliferation, angiogenesis, and metastasis of cancer cells leading to cancer progression. Given the important role of Cu in the onset and progression of cancer, targeting Cu homeostasis has emerged as a novel strategy in the treatment of cancer (Li, 2020; Michniewicz et al., 2021).

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).

Here, 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.

Dietary supplementation and absorption in the stomach, duodenum and upper small intestine is the main source of Cu in humans. Most of the absorbed Cu is stored in the liver and the Cu concentration in serum is approximately 12.0–25.0 μmol/L and varies in tissues between 15.0 and 180.0 μmol/g (Table 1). In physiological conditions the transport of Cu is strictly controlled. Cu is always bound to proteins to prevent excess redox activity and its distribution is precisely regulated by several cellular mechanisms. In mammalian cells, intracellular Cu intake is regulated by copper transport protein 1 (Ctr1) and Cu enters the cells in reduced form [Cu(I)]. Once inside the cell, Cu is bound to Cu chaperons or glutathione (GSH) and trafficked to metallothionein or distributed to specific compartments of the cells. Despite being an essential micronutrient, free Cu can induce toxicity to cells (Wee et al., 2013; Michniewicz et al., 2021).

Many studies have indicated that the levels of Cu in both serum and tumour tissues are remarkably elevated in cancer patients in comparison to healthy individuals as summarised in Table 1. Significantly higher Cu levels in serum have been associated with multiple cancers such as breast, cervical, ovarian, lung, gastric, bladder, thyroid, oral, pancreatic, head, and neck cancer (Li, 2020; Shanbhag et al., 2021). In some malignancies like colorectal cancer and breast cancer, elevated Cu levels are strongly correlated with the stage and progression of the tumours (Gupta et al., 1993; Sharma et al., 1994). On the other hand, in haematological cancers, a reduction in Cu levels was observed during periods of remission in patients, indicating that the distribution of Cu is altered in cancer patients (Kaiafa et al., 2012).

Although the underlying mechanisms alter the Cu levels in the serum of cancer patients remain unclear, the role played by Cu in etiology and progression of tumours has been widely studied in the past two decades. Exposure to high levels of Cu has been linked with pancreatic neuroendocrine tumours and prostate cancer (Ishida et al., 2013; Vella et al., 2017). As a metal able to induce redox reactions, Cu is capable of generating reactive oxygen species (ROS) in the intracellular environment that leads to activation of various pro-oncogenic signalling mechanisms that enhances the proliferation of cancer cells (Prasad et al., 2017). It has been recently shown that Cu is involved in the regulation of MAP kinase pathway and oncogenic BRAF signalling that regulates cell proliferation, differentiation and motility, by interacting with MEK-1 protein, a key penultimate kinase in the MAPK pathway. MEK-1 contains a high affinity Cu binding site, which, upon binding of Cu will stimulates the MEK-1 dependent phosphorylation of ERK1/2, ultimately promoting tumour proliferation (Brady et al., 2014).

Recently it has been shown that enhanced levels of Cu upregulate the expression of programmed death ligand 1 (PD-L1) in tumour cells and modulate the signalling pathways that mediates the PDL-driven immune escape by cancer cells (Voli et al., 2020). It has also been shown in the same study that chelators of Cu enhanced the ubiquitin-mediated degradation of PD-L1 and resulted in the infiltration T lymphocytes and natural killer cells in the tumour site, thereby suppressing tumour growth and improving survival in mouse models (Voli et al., 2020).

Cu has the ability to switch on many pro-angiogenic responses and aid the proliferation and mobility of endothelial cells, which initiates angiogenesis that provides oxygen and essential nutrients to tumours (Finney et al., 2009; Xie and Kang, 2009). Cu is considered as a key angiogenic messenger, because it can stabilise nuclear hypoxia inducible factor-1 (HIF-1), leading to expression and activation of several angiogenic factors including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), tumour necrosis factor alpha (TNF-α), interleukins 6 and 8 (IL-6, IL-8), and fibronectin (Martin et al., 2005; Feng et al., 2009; Rigiracciolo et al., 2015). Cu also promotes the remodelling of extracellular matrix through activation of the Cu-dependent enzyme lysyl oxidase (LOX). Similarly, another Cu-dependent protein known as superoxide dismutase-1 (SOD1) which is a regulator of vasoconstriction and endothelial function, is overexpressed associated with elevated Cu levels in cancers, which eventually stimulates VEGF production and enhances FGF-induced angiogenesis and tumour development, while a decrease in SOD1 activity has been shown to impair angiogenesis (Xiao and Ge, 2012; Shanbhag et al., 2019). In addition to the above, Cu is also shown to enhance the metastatic potential of cancers through activation of metabolic proteins such as (LOX) and lysyl oxidase-like (LOXL) which are involved in remodelling extracellular matrix and creation of pre-metastatic niches that harbours metastatic cancer cells (Salvador et al., 2017). 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 domain-containing 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).

Cu homeostasis in cancers is emerging as an attractive target for anti-cancer drug development. There are two main approaches that have been tested in both preclinical and clinical conditions. 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 therefore exert antitumor effects through ROS production, proteasome inhibition, and apoptosis induction (Li, 2020). Cu chelators such as D-penicillamine (D-pen), tetrathiomolybdate (TM), and trientine, are being widely investigated for their anticancer activity both in vitro and in vivo as well as in clinical trials (Wadhwa and Mumper, 2013). D-pen is a very strong metal chelator identified in early 1950s. D-Pen has the ability to remove Cu in vivo and the combination of D-pen and Cu could lead to cell death in endothelial cells and lymphocytes possibly as a result of ROS production and LOX and ICAM inhibition, eventually suppressing tumour growth and vascularization (Lipsky and Ziff, 1978; Starkebaum and Root, 1985; Brem et al., 1990; Gupte and Mumper, 2007). TM is another highly specific chelator of Cu and its anticancer activities has been studied well since the 1990s. TM has been demonstrated to inhibit angiogenesis in tumours by targeting multiple pathways including the suppression of NF-κB, HIF1α, LOX and SOD1 activities (Brewer, 2003). More recently, it has been shown that TM can inhibit MEK1/2 kinase activity by reducing the levels of intracellular Cu, and eventually suppressing BRAF-driven tumorigenesis in melanoma, thyroid and colon cancers (Kim et al., 2020; Xuefeng et al., 2020). TM can also enhance the cytotoxicity of BRAF-specific inhibitors like sorafenib. Trientine is another Cu chelator developed in the late 1960s, which has weaker activity than TM and D-Pen but is more tolerable than the other two in patients. The polyamine structure of trientine promotes Cu elimination via urinary excretion. It has been shown that trientine can inhibit endothelial cell proliferation by reducing the levels of IL-8 and CD31 expression (Moriguchi et al., 2002; Yoshiji et al., 2005).

While more research and encouraging clinical trials are ongoing for Cu chelators, Cu ionophores are also being widely studied for their anticancer activities. The mode of action of Cu ionophores is highly dependent on Cu as the compounds on their own have very little anticancer effect. Examples of Cu ionophores include Clioquionol, docosahexaenoic acid, thiosemicarbazone and DSF. Mechanistically these compounds exert their anticancer activities by elevation of extracellular and intracellular ROS, DNA damage and proteasome inhibition (Cater and Haupt, 2011; Yu et al., 2017; Sun et al., 2020). Clioquinol was shown to induce caspase-dependant apoptosis, but its clinical use has been discontinued due to its neurotoxicity (Cater and Haupt, 2011). Preclinical studies using analogues of Cloquionol are ongoing with different routes of administration for better anticancer activity and safety (Wehbe et al., 2018).

Among these compounds, DSF is the most extensively studied compound. DSF is also an attractive compound because of its established safety profile, easy availability, low cost, and less adverse effects than anticancer drugs. DSF can specifically carry Cu ions into tumour tissue, thereby preventing nonspecific interactions (Ekinci et al., 2019). Recently, some studies investigated the action of Cu complexes formed by some Cu-binding compounds such as DSF derivatives and its metabolites. Many clinical trials of DSF and Cu in combination with or without conventional anticancer drugs are under way which will be reviewed and summarised in the later part of this review.

From boosting immune system to targeting key molecules and developing personalized therapy cancer drug development is at its exciting phase today. New drug development is an expensive process, costing over $1.5 billion and taking approximately 15 yr to complete the process, however, there is a very high failure rate of up to 95% (Bertolini et al., 2015). Costs of this magnitude arrest research and development, forcing pharmaceutical developers to pitch for more money or suspend development altogether. Consequently, some of these new therapies reach price tags of more than $100,000 per patient per year, but still has no “meaningful benefit” (Saluja et al., 2018; Leighl et al., 2021). The prices of cancer drugs have increased 10% every year between 1995 and 2015 due to the escalated expense of R&D in the pharmaceutical industries (Leighl et al., 2021). In recent years there has been an increasing appreciation of the potential of repurposing known drugs like DSF, as an anticancer treatment. The approach is pointed towards developing cheaper alternative over the expensive ineffective drugs and reduce the burden on healthcare systems, while providing effective treatment options for thousands of patients diagnosed every year (Lu et al., 2021).

Although DSF shows high in vitro toxicity in cancer cells, there was almost no positive clinical data published in cancer patients https://clinicaltrials.gov/ct2/results?term=disulfiram+AND+cancer&Search=Search). A summary of all the clinical trials using oral DSF is given in Table 2.

This inefficiency of DSF could be attributed to the very short half-life of the currently available oral version of DSF in the blood stream which is approximately 2–4 min (Marselos et al., 1976; Eneanya et al., 1981; Johansson, 1992). Our previous findings indicated that the cytotoxic effect of DSF on cancer cells is executed in two phases: 1) The instant ROS mediate damages induced by the reaction between DSF and Cu; 2) A delayed killing induced by the end product, Cu-DDC (Butcher et al., 2018). After ingestion of the current oral version, DSF is rapidly reduced into two DDC molecules via the disulphide bond breakage in the gastrointestinal system and the bloodstream of the portal vein (Johansson, 1992). The DDC which is accumulated in the liver is still a highly reactive chelator of divalent metal ions, specifically Cu and Zn. But in the liver DDC is rapidly degraded into carbonyl disulphide and dimethylamine or undergoes methylation enzymatically to form S-methyl-DDC (Johansson, 1992; Butcher et al., 2018). As a result, DDC and all metabolites of DSF lose their active functional thiol groups and their ability to chelate with Cu or other metal ions is compromised. Surprisingly this process does not inhibit the anti-alcohol dependency activity of DSF as the metabolization of DSF takes place in the liver, which is the site of ethanol breakdown and hence it is able to successfully inhibit ALDH activity (Marselos et al., 1976; Eneanya et al., 1981; Petersen, 1992; Lewis et al., 2014). Whereas in the case of cancer, the reaction of DSF and Cu must take place inside or adjacent to cancer cell but mostly the target tissue where tumour is located are at a distant site. Hence the active sulfhydryl groups in DDC are indispensable for the chelation reaction between DDC and Cu and formation of Cu-DDC complex (Liu et al., 2014; Butcher et al., 2018).

Therefore, we hypothesised that using nano-drug-delivery system to protect the sulfhydryl groups in DDC will overcome the discrepancy between the anticancer activity of DSF in laboratory and clinic and pave the path between “bench and bed.” Based on this hypothesis, our group first encapsulated DSF into liposomes and demonstrated significantly improved anticancer efficacy in mouse models (Liu et al., 2014). Development of novel formulations of DSF using nano-drug delivery strategies will be of significant clinical importance in translation of DSF into cancer treatment (Figure 4).

The use of nanotechnology, a booming field in the last decade, could provide us with a cutting-edge drug delivery system for translating DSF into cancer treatment. There are various methods such as adjusting the formulation, structural modification, or encapsulation techniques, all of which aims at increasing the bioavailability of the interested compound. Nanoencapsulation involves the use of biodegradable compounds such as liposomes, polymers, polymeric micelles or protein (albumin) particles to encapsulate the drug of interest (Shi et al., 2017). Several FDA-approved formulations of nano encapsulated conventional anticancer drugs such as albumin nanoparticle Nab-paclitaxel (Abraxane™) and liposome encapsulated doxorubicin are currently used in the clinics. A summary of various strategies developed by different groups for delivering DSF is given in Table 3.

Polymeric nanoparticles are simple in design and encompass extensive structural diversity, outstanding bio-compatibility and stability (El-Say and El-Sawy, 2017). One of the best examples of polymeric nano encapsulation is PLGA. It was demonstrated that PLGA encapsulation shielded DS from breakdown in the bloodstream and transported the intact DSF to cancer tissues (Wang et al., 2017b). The efficacy of PLGA-based DSF nanoparticles was demonstrated in a wide range of cancers using xenograft mouse models of hepatocellular carcinoma, lung cancer, ovarian cancer, and breast cancer (McConville et al., 2015; Fasehee et al., 2016; Wang et al., 2017a; Fasehee et al., 2017; Najlah et al., 2017). In addition, polymeric nanoparticles can be modified extensively to add functional groups that can be targeted for delivery to a tissue of interest. For example, a folate receptor targeted PEG-PLGA was shown to deliver and enrich DSF specifically to breast cancer tissues while avoiding degradation of DSF in the bloodstream (Fasehee et al., 2016). Our group developed DSF loaded PLGA nanoparticles through emulsion-solvent evaporation method with excellent entrapment efficiency and better drug loading. The nanoparticles were in the size range of ∼136 nm and had significantly extended the half-life from 2 min to 7 h in serum. The encapsulated DSF also demonstrated a significant synergistic cytotoxicity in combination with 5-FU or sorafenib and inhibited the growth of cancer stem cell populations in liver cancer models and reduced the metastatic activity and recurrence in mouse HCC xenograft and metastatic models (Wang et al., 2017b).

Liposomes which are artificial spherical vesicles prepared from naturally derived phospholipids are the most widely investigated and well-established drug delivery carriers used in clinics to treat various cancers due to their biocompatibility, specifically being non-immunogenic, non-toxic, and biodegradable. In addition, liposomes serve as sustained release systems providing protection against degradation and increased the time in circulation (Moosavian et al., 2021; van der Koog et al., 2021). In this sense, our group recently demonstrated that liposome encapsulated DSF a relatively extended half-life in serum and a significantly increased anticancer efficacy in in vitro and in vivo breast cancer mouse models (Liu et al., 2014).

Considering the hydrophobic nature of DSF, liposome-based delivery system would be an exciting prospect. Our group has developed liposome encapsulated DSF which shows significantly improved anticancer efficacy in breast cancer and sarcoma mouse models (EP2648709B1, 2011; Liu et al., 2014). Recently, we also encapsulated DSF into a PEGylated liposomal formulation of DSF using ethanol-based proliposome technique followed by high-pressure homogenization with significantly improvement in the stability of DS in serum and effective cytotoxicity to colorectal cancer cell lines in the presence of Cu in vitro (Najlah et al., 2019). Another group has developed an encapsulated formulation of DSF and doxorubicin which reduced the expression of P-gp and increased the efficacy of doxorubicin in breast cancer cells (Rolle et al., 2020). Banerjee et al. (2019) has shown that a formulation of nanostructured lipid carriers (NLC) encapsulated DSF modified with d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E-TPGS) showed an enhanced uptake in breast cancer cell lines and significantly reduced the tumour size and enhanced tumour suppression in xenografted mouse models (Banerjee et al., 2019).

Micelles have unique properties such as low molecular weight, better entrapment and enhanced delivery in tumour sites and are very suitable for a hydrophobic drug like DSF. They can easily penetrate the tumour tissue in comparison to other nanoparticles (Deshmukh et al., 2017). Our group developed a Pluronic micelle formulation to deliver DSF for triple negative breast cancer treatment. However, the main drawback of using micelles for DSF is their stability. Duan et al. developed a micelle cross-linked with redox sensitive shells that delivers DSF in reduced environments of the tumours (Duan et al., 2014). Another modified version of micelles using PEG and poly-lysine copolymers blocks were also used for delivery of DSF and paclitaxel together for tackling multidrug resistance and P-gp inhibition in breast cancer models and resulted in enhanced uptake of paclitaxel by breast cancer cells (Huo et al., 2017).

There are also more unique methods of delivering DSF; for example, magnetic mesoporous silica nanoparticles were used to specifically deliver DSF to breast cancer cells (MCAF) in vitro (Solak et al., 2021). DSF has also been loaded onto gold nanorods with a reported a drug loading content of up to 23.2% (Xu et al., 2020a). The Au-DSF product was able to effectively increase ROS and induce apoptosis in breast cancer cells in vitro.

Albumin is a promising macromolecular drug carrier as it is biocompatible, biodegradable, non-immunogenic and soluble in water to allow for injection. In addition to this, it is possible to modify the surface of albumin nanoparticles for targeting. Previously, nanoparticle albumin bound technology has been used to solubilize the hydrophobic cancer drug paclitaxel (Abraxane) which is now a first line drug for PDAC (Stinchcombe, 2007). Since the complexes Cu(DDC)₂ and Zn(DDC)₂ are hydrophobic; nanoparticle albumin bound technology may be the key to develop an injectable, long circulating formulation.

Cu(DDC)₂ and Regorafenib (Rego) were successfully encapsulated in bovine serum albumin (BSA) nanoparticles via denaturation of BSA by urea (Zhao et al., 2017). The formulation targeted secreted protein acidic and rich in cysteine (SPARC) receptors. Furthermore, mannose receptors were targeted by modifying the surface of the BSA nanoparticles. It had enhanced anti-cancer efficacy in an animal model bearing resistant tumours via apoptosis, upregulation of intracellular ROS, anti-angiogenesis and tumor-associated macrophage repolarization. These nanoparticles could also effectively cross the blood brain barrier to deliver Cu(DDC)₂ and Rego to treat gliomas in mice (Zhao et al., 2018). The option to selectively target cancer cells by modifying the surface of the BSA nanoparticles could be vital when delivering DDC already complexed with Cu compared with DSF alone. DSF targets cancer cells due to their increased levels of Cu. On the other hand, a Cu(DDC)₂ complex may have increased toxicities on normal cells. Another suitable macromolecule carrier for DSF is Cyclodextrans (CDs) which are cyclic oligosaccharides that can form truncated-cone-shaped macrocyclic molecules that possess hydrophobic cavities. These cavities can solubilize hydrophobic drugs and Suliman et al. (2021) developed a CD formulation of Cu(DDC)₂ and demonstrated stability for 28 days with enhanced cytotoxicity against resistant breast cancer cell lines (Said Suliman et al., 2021).

Together, all the above evidence has indicated that using nanotechnology-based formulation strategies can significantly improve the half-life, stability, bioavailability and it is possible to achieve delivery of DSF at therapeutic doses in cancer patients.

The success of platinum drugs has led to the search for metal complex-based anticancer therapeutics. The search for novel metallodrugs or metal complexes that target cancers is still a field of high interest in the pharmaceutical sector. The fundamental role of Cu in aiding cancer progression and the dysregulation of Cu homeostasis in cancers has been well documented in both preclinical and clinical settings. With Cu as an emerging novel target, there has been major advancements in the development of Cu coordination complexes as anti-cancer therapeutics. Use of Cu chelators and Cu ionophores have yielded encouraging anticancer activities in many preclinical models. Particularly many drugs that are used for other indications have been identified and repurposed as Cu coordination drugs, not only to achieve better antitumour efficacy, but also to enhance the efficacy of first line anticancer drugs such as platins.

Among many repurposed metal chelator drugs, DSF has a great promise and potential to be used as an anticancer agent. With its anti-angiogenic potential, and the ability to target CSCs and synergistically potentiate many first line conventional drugs, DSF could provide new opportunities to develop effective combination therapeutic strategies. DSF also has a great potential be an effective immunomodulatory drug by regulating NF-kB signalling or by reducing PDL-1 expression by Cu chelation. In this review we have summarised the effectiveness of DSF as an anticancer agent, which applies to a wide range of cancers. Despite several clinical trials, no reliable efficacy of DSF as an anticancer drug for tumours has been observed due to the lack of biological availability and short half-life of the currently available oral DSF. Therefore, the development of an appropriate formulation is critical for the successful translation of DSF into cancer indication. Here we summarized different delivery strategies that have been developed for DSF-based cancer therapy. Most of the identified or developed drug delivery systems for DSF are at the proof-of-concept stage either in in vitro studies or in vivo pre-clinical animal models. Although many of these delivery strategies demonstrated great potentials for DSF as an anticancer agent, these delivery systems must be extensively evaluated with further studies to gather complete preclinical information such as safety, toxicology, pharmacokinetic and optimal physicochemical properties which are crucial to facilitate clinical translation.

Although many different delivery strategies using novel materials indicated additional benefits, the use of FDA approved excipients could minimize regulatory hurdles and considerably reduce the preclinical development time. Moreover, the development of encapsulation strategies should be suitable for scale-up production for manufacturing and commercialization. In addition to these technical issues, there are many regulatory and marketing hurdles for commercialization of DSF based anticancer product, predominantly due to the lack of patent protection on DSF.

Therefore, pharma companies do not show much interest to invest in clinical trials for DSF-based anticancer therapeutics. The development of novel formulations of DSF together with appropriate strategies for exploitation of regulatory guidelines, would lead not only to the development of intellectual properties and enhanced anticancer efficacy, but also will lead to the successful development and clinical translation of DSF as an anticancer product for commercialization.