There has been tremendous progress in the fields of drug discovery, tumor biology, nanomedicine, and targeted drug delivery for improving treatment and patient care, yet cancer remains one of the leading causes of death. The process of discovering new chemical entities and their development into anticancer drugs can be very time consuming and expensive. Drug repurposing via new drug delivery systems is a relatively less time-consuming, simple, and cost-effective strategy in treating many diseases [1,2]. With the advancement of computational and rapid screening technologies, new drug candidates are now available for cancer treatment. However, the efficient delivery of these drugs to cancer tumors still requires novel drug delivery devices and methods [3,4].

Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumor cells [5]. However, copper chelation has been reported to produce a decrease in the secretion of many of these factors [5,6]. Recently, Based on clinical data indicating that elevated serum copper levels associated with many cancer tumors, many copper chelators are being developed and tested in clinical trials in recent years [7]. Although it remains to be determined the mechanism which copper chelation suppresses the growth of endothelial cells and hinders the secretion of angiogenic factors by tumors is not entirely clear, it is has been hypothesized to result from effects on copper-dependent enzymes, transporters, and chaperones [8].

Recently, a novel cell death pathway, distinct from apoptosis, necroptosis, pyroptosis, and ferroptosis, induced by copper, has been identified, and designated as cuproptisis [9]. Cuproptosis is significantly correlated to cellular metabolism and is frequently observed in certain types of cancer that have high levels of aerobic respiration, including melanoma, breast cancer, leukemia, and drug-resistant cancers [10]. Copper ionophores have played a crucial role in the identification of cuproptosis and have been considered as possible anticancer treatments [11,12]. Diethyldithiocarbamate (DDC), an active metabolite of the drug, disulfiram (DSF), has been reported to be a copper ionophore that has in vitro and in vivo efficacy as an anticancer compound. [11].

Disulfiram (DSF,) is a thiocarbamate derivative that has been used to treat alcoholism since 1951 [13]. DSF inhibits the enzyme aldehyde dehydrogenase 1 (ALDH1), which significantly inhibits the biotransformation of ethanol to ethanol at the acetaldehyde stage [14], thereby increasing the levels of ALDH1, which produces various adverse effects following the ingestion of ethanol, decreases or discourage ethanol intake [15]. Interestingly, ALDH1 is present found in cancer cells with stem cell properties, and it catalyzes the oxidation of intracellular aldehydes and produces multidrug resistance [16]. Subsequently, clinical data suggested that DSF had anticancer efficacy [17]. In addition, DSF was shown to regulate the balance of reactive oxygen species (ROS) and glutathione (GSH) [18], inhibit the activity of the ubiquitin proteasome system (UPS) [19], and regulate intracellular signaling [20,21] and the activity of other enzymes, which could play a role in mediating its anticancer efficacy [22,23,24]. Indeed, these mechanisms could induce cancer cell death, decrease the stemness of cancer cells [25], decrease angiogenesis, and overcome drug resistance [26,27].

As mentioned earlier, trace metals are essential for the survival of cancer cells [28,29]. Compared with normal cells, many tumor cells have a 2–3-fold higher concentration of copper [30]. DSF is a potent chelator of copper, and DSF can bio-transform the pro-angiogenic activity of copper to a specific compound that induces cancer cell death [31]. Although DSF has shown promise in both laboratory and animal studies, certain clinical trials with cancer patients have been unsuccessful due to treatment requiring high doses and the expectation partially owing to the rapid biodegradation of the DSF [32,33]. Cu (II) chelation of the primary DSF metabolite, diethyldithiocarbamate (DDC), is crucial for inducing the death of tumor cells [34,35]. The copper-dependent anticancer efficacy of DSF has resulted in an increase in research related to DSF/Cu (II) [36,37]. DSF/Cu (II) has been reported to be efficacious in a variety of cancers, including liver cancer [38], ovarian cancer [39], prostate cancer [25], lung cancer [40], glioblastoma (GBM) [41], and breast cancer [42] (Figure 1). The anticancer efficacy of DSF is most likely due to the bio-transformation of DSF to diethyldithiocarbamate (DDTC), which forms an intracellular copper–DDTC complex (Cu(DDTC)₂), which has been shown to be the most efficacious anticancer compound [43]. DSF can induce ferroptosis and cuproptosis in different types of cancer cells [44]. A summary of various clinical trials assessing the efficacy of DSF-based cancer is shown in Table 1. Some clinical trials have investigated the use of DSF for treating solid tumors, with some reporting improved progression-free survival and overall survival, compared the control groups. Adverse effects were generally mild and resolved following a decrease in the dose of DSF. Two single-arm trials in glioblastoma patients showed positive effects, while a randomized controlled trial in NSCLC patients also reported an increase in patient survival [45,46,47]. However, the response to DSF varied among patients, and further in vitro and animal studies are needed to explore the optimal concentration and sensitivity type. Overall, DSF appears safe and effective in prolonging survival in cancer patients [48].