Curcuminoids and Dimethoxycurcumin as Therapeutic Agents in Melanoma: Focus on Metastasis and Primary Care Integration

ABSTRACT

Melanoma is a type of skin cancer associated with the uncontrolled growth of melanocytes, the pigment‐producing cells. This type of skin cancer continues to be a major concern owing to its strong tendency to spread. Melanoma progression is influenced by the activation of various signalling pathways, such as PI3K/AKT/mTOR, MAPK/ERK, and Wnt/β‐catenin pathways. Curcuminoids, derived from turmeric, are known for their anti‐inflammatory and antioxidant properties and influence the PI3K/AKT/mTOR pathway by acting on key molecules, such as mTORC1, PI3K, and AKT. Curcuminoids have demonstrated reduced ERK phosphorylation, which lowers MAPK pathway activity. Additionally, curcuminoids have been shown to block the cell cycle at the G₂/M phase and consequently inhibit Wnt/β‐catenin pathway signalling. This review aims to explore the potential use of curcumin, bisdemethoxycurcumin, demethoxycurcumin, and a synthetic analogue of curcumin, dimethoxycurcumin, in combating melanoma. This review stands out by comparing natural and synthetic curcuminoids against the signalling pathways that drive melanoma. The abovementioned curcuminoids and synthetic analogue have shown anti‐cancer potential by targeting key molecular targets implicated in the PI3K/AKT/mTOR, MAPK/ERK pathways, paving the way for potential novel treatment approaches. Additionally, this review addresses the sustainable development goals and the role of curcuminoids in primary health care.

Significance Statement

• Melanoma remains a highly aggressive skin cancer with rising incidence across Southern Africa, mirroring trends in the USA and Australia.

• Given the therapeutic limitations of current modalities, integrating phytochemicals, such as curcuminoids, as adjunct therapies offers a promising strategy.

• Natural curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) have demonstrated widespread efficacy.

• Thus, this review explores their potential additive and synergistic combinations.

• Additionally, we evaluated a synthetic analogue, dimethoxycurcumin, designed to overcome poor bioavailability.

• Beyond oncology, these affordable, low‐toxicity compounds support Sustainable Development Goal 3 by expanding treatment access in resource‐limited regions.

• Furthermore, their plant‐derived nature aligns with eco‐friendly drug development.

• Realising these clinical benefits ultimately relies on cross‐sector collaboration, in line with Sustainable Development Goal 17.

1. Introduction

Cancer is the result of rapid and uncontrolled cell division and can potentially metastasise throughout the body [1]. Melanoma, a type of cancer characterised by the irregular growth of melanocytes, also known as skin cells, arises primarily due to excessive exposure to ultraviolet (UV) rays [2]. The age‐standardised incidence rate for melanoma and non‐melanoma skin cancers (NMSCs) in both males and females is equal to or more than 19.8 per 100,000 in the United States of America, Australia and South Africa [1]. Based on the abovementioned statistic, South Africa not only has the highest age‐standardised rate (ASR) across the African continent, but is also internationally comparable to those of the United States and Australia [1]. Melanoma holds a 20% mortality rate globally and accounts for 80% of fatalities caused by skin cancer [3, 4]. This increase in percentage is driven by the metastatic potential of melanoma and its resistance to treatment [3].

Current melanoma treatment regimens include a multimodal therapeutic approach to overcome treatment resistance. Targeted immune therapies represent more recent and promising therapies for cancer treatment [5]. The first‐line treatment for advanced metastatic melanoma includes immuno‐ and targeted therapies [6]. These treatment modalities have improved overall survival by ten times compared to previous outcomes [6]. However, current treatment options have shortcomings, including adverse effects involving the gastrointestinal tract and dermatological implications [3, 6]. Treatment for current modalities may lack efficacy, therefore, adjuncts, such as phytochemicals, may offer promise.

Curcumin (CUR) is the principal curcuminoid isolated from Curcuma longa, commonly known as turmeric [7]. Curcumin has been acknowledged for its anticancer, antioxidant, and anti‐inflammatory effects [7]. The family of curcuminoids found in turmeric includes CUR, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Curcuminoids have been studied for their anticancer potential in various cancer types including melanoma, prostate and breast cancer, head and neck cancers as well as glioblastoma [7, 8]. However, the use of curcumin has been limited due to its low bioavailability and poor solubility in aqueous solutions [8]. Nevertheless, many of its metabolites demonstrates physiological and therapeutic properties [8].

Therefore, this review explores the use of turmeric and its natural curcuminoids, as well as the synthetic compound DiMC, in relation to their potential anticancer effects on melanoma progression. The review also discusses curcuminoid delivery systems used to enhance its solubility. Although CUR is widely recognised for its anticancer effects, it also has broader relevance for global health. Its relatively low toxicity, affordability, and potential use in primary care make it a promising option for improving access to cancer treatment, particularly in resource‐limited regions, tentatively linking to Sustainable Development Goal 3. Furthermore, because it is plant‐derived and can be produced using more sustainable methods, CUR offers possibilities for environmentally responsible drug development. However, translating these benefits into real‐world clinical use will depend on strong collaboration among researchers, clinicians, and industry partners, underscoring the importance of Sustainable Development Goal 17.

2. Melanoma Tumour Microenvironment

2.1. Significance of Neovascularisation and Tumour Angiogenesis

Neovascularisation, the formation of new blood vessels, is a critical process that drives metastasis [9]. As a result, neovascularisation ensures that tumours receive adequate oxygen and nutrients while discarding metabolic waste products. Tumour cells migrate from their initial site to form tumours at secondary sites by using the lining of newly formed blood vessels [9]. This, in turn, can lead to the downregulation of the tumour immune response by repression of antigen presentation and dendritic cell (DC) maturation [9]. Tumour neovascularisation also interferes with the attraction of immunosuppressive cells, such as natural killer (NK) cells and DCs, and reduces the activity of cytotoxic T cells [9]. Accordingly, the tumour microenvironment (TME) plays a key role in producing multiple factors that stimulate tumour angiogenesis, developing a self‐sustaining cycle that supports invasive tumour growth [9]. It is important to understand that neovascularisation includes all ways new blood vessels form in tumours whereas tumour angiogenesis is the growth of new blood vessels from existing ones [10]. During the onset of cancer, tumorigenic cells, as well as fibroblasts and immune cells, secrete pro‐angiogenic factors, which activate endothelial cells, allowing more blood and nutrients to reach the tumour [11]. Therefore, inhibiting neovascularisation and, as a result, angiogenesis seems to be promising targets to limit tumour growth.

2.2. Immune Cells and Key Molecules in the Tumour Microenvironment

Tumour cells attract healthy cells to the tumour site, forming a complicated structure of both malignant and non‐mutated cells [12]. This forms the TME, which consists of various components such as fibroblasts, tumour cells, macrophages, endothelial cells, and the extracellular matrix (ECM) [13]. The TME plays a crucial role in enabling metastasis, as all the TME‐associated cells may stimulate neovascularisation through the activation of signalling pathways. Additionally, tumour cells can form patterns mimicking real blood vessels, allowing a sufficient supply of nutrients when the normal blood supply is inadequate [11]. This phenomenon, in which tumour cells imitate blood vessels, is known as vasculogenic mimicry, significantly driving tumour progression [11].

As melanoma progresses from its initial stages, immune cells, such as macrophages, NK cells, neutrophils, and DCs, are elevated, leading to possible apoptosis, release of cytokines, and direct attack on cancer cells through cytotoxic reactions [14]. Natural killer cells secrete cytokines to signal and activate antigen‐presenting cells (APCs) [14]. T cells play a critical role in combating melanoma. Cluster of Differentiation 8 positive (CD8 + ) T cells identify cancer related markers on melanoma cells and consequently aid in killing those cells, while CD4 + T helper (Th) cells interact with APCs to help coordinate an immune response based on the cytokines released by the tumour [14].

Melanoma cells exhibit extensive cellular flexibility and therefore, find various ways to escape the immune system [15]. Firstly, these cells decrease the expression of major histocompatibility complex molecules (MHC), which are responsible for displaying antigens to the immune system [16]. Additionally, T cells express programmed cell death protein (PD‐1) on their surface, and melanoma cells take advantage of this by producing more programmed death‐ligand 1 (PD‐L1) [17]. This, in turn, inhibits the activity of T cells, leading to their destruction. Melanoma cells also convert T helper (Th) cells into regulatory T cells, resulting in an overall weakened immune response [15].

Furthermore, tumour cells release exosomes, which are small particles that carry proteins and genetic material, throughout the body, which are then taken up by cells in distant parts of the body [18]. Exosomes can reset recipient cells to create an environment that supports tumour development. These recipient cells then release molecules like matrix metalloproteinase‐9 (MMP‐9), which aids in tissue remodelling and the breakdown of blood vessels, making it easier for circulating tumour cells (CTCs) to establish at these distant sites [19, 20]. Additionally, exosomes aid in phenotype switching and dormancy, ensuring tumour spread and that the tumour remains dormant until the environment is optimal [18, 21].

Finally, chronic inflammation can sustain tumour growth [22]. Tumours release inflammatory molecules that favour tumour survival. These molecules include chemokines, cytokines, and prostaglandins [23, 24]. Cyclooxygenase‐2 (COX‐2) plays a crucial role in tumour progression and development, and high levels thereof have been identified in human and murine melanoma cases [25]. Elevated COX‐2 levels promote angiogenesis, inhibit apoptosis, encourage immunosuppression, aid in the production of DNA‐damaging substances, and contribute to treatment resistance [22, 26]. Additionally, prostaglandin E2 (PGE₂), made from arachidonic acid in a reaction catalysed by COX‐2, contributes to tumour aggressiveness and treatment resistance [22]. As a result, inhibiting inflammation by targeting COX‐2 could be a promising strategy for cancer treatment and prevention. Moreover, COX‐2 upregulates vascular endothelial growth factor (VEGF) expression via the phosphoinositide 3‐kinase (PI3K) pathway, resulting in enhanced angiogenesis [22]. Matrix metalloproteinase 14 and 2 are stimulated by COX‐2. These MMPs aid in tissue breakdown and therefore accelerate metastasis [22, 27]. Matrix metalloproteinase 14 and 2 also aid in vascular mimicry, further sustaining tumour progression [28].

In addition, the mitogen‐activated protein kinase (MAPK) pathway plays a key role in melanoma [22]. Elevated MAPK pathway activity leads to increased activator protein‐1 (AP‐1) [22]. This transcription factor promotes COX‐2 production, cell division, and inflammation, further contributing to tumour development [22]. MAPK pathway activation stimulates the release of interleukin‐1α/β (IL‐1α/β) inflammatory signals [22]. This, in turn, triggers fibroblasts to produce COX‐2 and PD‐1, which leads to immunosuppression [22, 29]. The c‐Jun subunit of the AP‐1 complex plays a key role in melanoma development as it leads to disrupted gene regulation in both MAPK and PI3K pathways [30]. These findings suggest that targeting AP‐1 could be a favourable approach, as decreased AP‐1 activity leads to decreased COX‐2 expression and subsequently decreased PGE₂ levels, thereby slowing down tumour progression. Considering this, it is crucial to account for the role of the TME when identifying novel molecular targets and exploring innovative treatment strategies.

3. Key Parameters of Melanoma Metastasis

3.1. Melanoma Metastasis and Immunological Implications

The migration of cancer to various secondary sites occurs via metastasis and is explained through five main steps. Firstly, invasion refers to the detachment of cancer cells from the original tumour, followed by the intravasation of cancer cells into the lymphatic system or bloodstream [20, 31]. Subsequently, these cells travel through the circulation and exit blood vessels at a new location during a process known as extravasation, which constitutes the fourth step in this process [20, 31]. Finally, these cells colonise new tissue to form secondary tumour sites [20, 31]. Epithelial‐mesenchymal transition (EMT) supports the aforementioned process of cancer metastasis. During EMT, there is a decrease in epithelial marker expression on cancer cells, such as E‐cadherin, which is responsible for cancer cell‐cell adhesion. In turn, cancer cells increase their expression of mesenchymal markers, such as N‐cadherin, which allows these cells to migrate easily [32]. This process is regulated by various transcription factors (TFs), including zinc finger E‐box binding homeobox (ZEB1/2) and Twist family bHLH transcription factor 1/2 (TWIST1/2) [20, 33]. During EMT, changes in adhesion molecules occur in both cancer cells and cancer‐associated fibroblasts (CAFs) [20]. However, EMT mainly occurs in carcinomas. Melanomas undergo phenotype switching [20, 34], which refers to the ability of melanoma cells to change their behaviour to survive in any environment. As a result, melanoma cells are more flexible and can alter their metabolism to utilise the minimum amount of glucose possible to survive, often referred to as the Warburg effect [20]. Melanoma cells also interact with CAFs and other types of cells in the tumour, which makes the tumour more adaptable [20].

Macrometastases, the formation of large tumours at secondary sites, is a complex process, as the environment beyond the TME is difficult to survive in [20, 35]. When melanoma cells survive outside the primary TME, they regularly enter a state of dormancy in which the focus is shifted to survival instead of proliferation [20]. Dormant tumour cells are paused in the G₀ phase of the cell cycle and remain inactive for long periods, and are thought to be the primary cause of late cancer metastasis [20]. Genes such as SMAD7, gelsolin, KISS1, and nm23 aid in keeping melanoma cells in a dormant state while in circulation [20, 36, 37]. A MAPK, p38, which forms a part of the stress‐activated protein kinase (SAPK) subgroup of MAPKs, aids in keeping cancer cells in a dormant state, whereas ERK induces cell growth [20, 38]. However, since common mutations that lead to melanoma, such as B‐Raf proto‐oncogene (BRAF) and neuroblastoma RAS viral oncogene homologue (NRAS), activate ERK signalling, it overrides dormancy maintained by p38 [38]. Dormant cells may be reactivated due to neovascularisation and alterations in the immune system [20]. Melanoma cells also engage in a process known as vasculogenic mimicry, in which they create new vascular networks lined with melanoma cells instead of endothelial cells [20, 39]. Melanoma cells can then initiate metastasis by entering the bloodstream as circulating tumour cells (CTCs), but most of these usually do not remain viable. Those that survive will then enter a dormant, low microphthalmia‐associated transcription factor (MITF) state, meaning that the focus is on survival rather than proliferation, and these cells tend to also be more resistant to treatments [20, 34, 40]. In BRAF‐ and NRAS‐melanomas, a protein known as AXL is upregulated and also coincides with a low‐MITF state, equipping these melanoma subtypes with prolonged viability, reduced sensitivity to treatments, and increased capacity to remain in a dormant state [20, 41]. Therefore, the plasticity of melanoma cells enables them to survive in various environments, making treatment a significant challenge. Conversely, dormancy escape is when melanoma cells alter their behaviour and energy metabolism, allowing them to resume active growth [20]. Nonetheless, for these cells to establish at a secondary metastatic site, they must also be equipped with the correct epigenetic reprogramming, adjusting the activity of genes, such as extracellular signal‐regulated kinase (ERK), SMAD7, and gelsolin, without altering the deoxyribonucleic acid (DNA) sequence [20, 42].

The mechanisms underlying melanoma progression are well understood. However, research into the molecular changes characterising this disease is still underway. A noteworthy protein, melanoma inhibitor activity (MIA) protein, is present in melanoma cells, but not in non‐cancerous cells [43, 44]. Its role extends beyond merely facilitating the migration and invasion of melanoma cells, as it is also involved in regulating various genes, such as matrix metalloproteinase 14 (MMP14) and fibronectin 1 (FN1), which affect cell structure, movement, and survival [43]. Therefore, MIA is an attractive target for therapeutic intervention. Furthermore, MIA serves as an indicator of disease presence [43, 44].

3.2. Anatomical Patterns of Melanoma Metastasis

In a study conducted by de la Monte et al., investigating the pattern distribution of malignant melanoma, it was found that, in most cases, the cancer initially spreads to the abdomen, chest, and central nervous system, which includes the brain and spinal cord [45]. More specifically, in the abdomen, melanoma primarily spreads to the liver, lymph nodes, digestive tract, and adrenal glands [45]. Similarly, in the chest, melanoma most often spreads to the lungs, heart, and lymph nodes in the chest [45]. Therefore, it is clear that lymph nodes are a major target of melanoma. Sentinel lymph node biopsies are key diagnostic and prognostic tools, as they provide insight into the likelihood of cancer metastasis [45, 46]. Melanomas frequently initiate lymphangiogenesis as a process occurring at the interface between the tumour and the surrounding tissue [46]. Tumours with a greater number of lymphatic vessels demonstrate an increased risk of metastasising to the lymph nodes [46]. Melanoma cells and macrophages release vascular endothelial growth factor‐C (VEGF‐C), which contributes to lymphatic vessel growth and negatively impacts patient prognosis [46]. Melanoma cells are known to partake in lymphovascular invasion, a consequence of lymphangiogenesis [47]. Lymphovascular invasion occurs when cancerous cells infiltrate small lymphatic or blood vessels in close proximity to the tumour [47]. Since this process initiates melanoma metastasis, it is an essential target for intervention.

3.3. Clinical Parameters of Melanoma

Melanomas are clustered based on their growth patterns. The four primary types include superficial spreading‐, lentigo maligna‐, acral‐, and nodular melanomas [48]. Melanomas typically grow in two directions: radial and vertical growth. The radial growth phase is characterised by flatter marks on the skin, and the cancer spreads along the epidermis [48]. During the vertical growth phase, the cancer penetrates deeper into the skin, suggesting that the tumour is becoming increasingly more aggressive [48]. On the skin, melanoma presents as irregular bumps with uneven borders and various discolouring patterns [48, 49]. The American Joint Committee on Cancer staging system (AJCC) provides insight into the staging of melanoma. Metastatic relapse is established according to Breslow depth, ulceration, mitotic rate and lastly lymph node involvement [48, 50]. When melanoma is restricted to the lymph nodes or skin, it is classified as stage III, but when it spreads to distant organs, it is considered stage IV [48].

Given the clinical significance of melanoma progression from localised to metastatic disease, understanding the underlying mechanisms of metastasis is critical for improving treatment outcomes. This is especially relevant in regions with high disease burden. In South Africa, which has the highest ASR of melanoma in Africa and globally, early detection through primary health care screening is vital. Integrating screening at the primary care level can enhance early diagnosis, thereby improving therapeutic efficacy and patient outcomes.

3.4. Melanoma Screening in the Primary Health Care Setting

Given that South Africa has the highest ASR of melanoma on the African continent and globally, early detection of melanoma is of great importance. Therefore, primary health care screening needs to be considered. Two useful tools for identifying new melanomas are sequential digital dermoscopic imaging (SDDI) and total body photography (TBP) [51, 52]. Sequential digital dermoscopic imaging involves capturing magnified images of individual moles at different times using a dermatoscope to detect subtle changes over time [53]. On the other hand, TBP consists of a series of full‐body photographs that document all of a person's moles [53]. By comparing these images taken at different times, clinicians can identify newly developed moles and notice changes in existing ones [53]. This combined use of SDDI and TBP is known as the two‐step digital monitoring method and is considered an effective approach for continuous monitoring in individuals at high risk of developing melanoma [51, 53]. In a study carried out by Nguyen et al., a group of high‐risk Australian patients were monitored with SDDI and TBP [53]. This study found that certain changes observed with dermoscopy were more frequently associated with melanoma, and similar findings have been reported in other studies. However, these results can vary because identifying dermoscopic features is somewhat subjective. Therefore, training artificial intelligence models to aid in identifying melanomas could offer breakthrough, however these models need to be trained and tested using a wide range of datasets [52]. Dermoscopic changes that aided in identifying melanomas included asymmetric enlargement, abnormal vessels, irregular pigmentation, and shiny white areas [53]. Overall, this screening method still proved to be effective since doctors and clinicians found a relatively high number of melanomas compared with the number of harmless moles they had removed [53].

These findings suggest that dermoscopy can help primary health care doctors determine which lesions require a biopsy. However, additional research is necessary to determine the required training and cost‐effectiveness of using dermoscopy in primary health care [54].

4. Turmeric (Curcuma longa)

Turmeric is a spice that was first used in India, and is extracted from the stem of a plant belonging to the Zingiberaceae family [55, 56]. Various phenolic compounds derived from phenylalanine and, to a lesser extent, from tyrosine are found in turmeric, which contributes to its anti‐migratory effects [57]. Turmeric is composed of three bioactive curcuminoids, which are responsible for its wide range of therapeutic effects [55]. Curcumin constitutes 77% of turmeric, while demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) make up 17% and 3% of turmeric, respectively [55]. Dimethoxycurcumin (DiMC), a synthetic derivative of CUR, has shown several promising therapeutic effects, which are later discussed in more detail [58]. Table 1 below compares the properties of the indicated curcuminoids and DiMC.

Table 1.

Comparative properties of selected curcuminoids and DiMC.

Curcuminoid	Potency of antitumour effect	Selective cytotoxicity	Stability	Bioavailability	Availability of in vivo evidence	Melanoma‐specific data	References
CUR	High. Suppresses tumour growth, angiogenesis, and key oncogenic pathways (β‐catenin, p38 MAPK, VEGF, TNF‐α, COX‐2, MMP‐2/9)	Yes. Selective cytotoxic to malignant cells (eg. B‐CLL, MCF‐7) while sparing non‐cancerous cells	Low. Metabolically unstable, with rapid systemic clearance	Low.	Supported by in vitro and in vivo studies and clinical trials	Directly evaluated in melanoma cell lines. Mitigates UV damage, suppresses pro‐tumorigenic cytokines (TNF‐α, IL‐6/8), and targets key oncogenic pathways	[55, 59, 60, 61, 62, 63, 64]
BDMC	Most effective. Most potent natural curcuminoid. Triggers ROS production, DNA damage, and BCL‐2/CBR‐2 dependent apoptosis	Yes. Induces CBR2‐dependent apoptosis, sparing non‐cancerous cells that lack CBR2 expression	High. More stable than CUR because of the lack of methoxy groups and autoxidation	Moderate	Indirect evidence. Data were extrapolated from non‐melanoma cell models (e.g., breast, colon, and leukaemia)	Extrapolated evidence. High CBR2 expression in malignant melanoma cells suggests therapeutic potential, but data are derived from other malignancies.	[55, 58, 65, 66, 67, 68, 69]
DMC	High. Inhibits invasion/metastasis (MMP‐9, ICAM‐1, CXCR‐4), inactivates IRS2‐PI3K‐Akt, upregulates WIF‐1, and induces G2/M arrest	Warrants caution due to off‐target G2/M arrest in non‐tumourigenic HaCaT keratinocytes	High. More stable than CUR due to single methoxy group loss.	Moderate.	Indirect evidence. Findings are derived from other cancer cell lines (e.g. ovarian, prostate, and breast).	Findings are extrapolated. Targets melanoma pathways (e.g. IRS2 in B16‐F10 cells, CXCR‐4, WIF‐1), but direct efficacy in melanoma cells warrants further testing.	[55, 58, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81]
DiMC	Very high. Synthetic derivative with superior NF‐kβ suppression, ROS production, and cytotoxicity compared to CUR and BDMC.	Yes. Selectively induces apoptosis and paraptosis in resistance cancer cells while sparing non‐malignant cells.	High. Shows superior stability due to its four methoxy groups within its synthetic structure.	Moderate to high.	Indirect evidence. Observed in renal, breast, and macrophage models.	Findings are theoretical. Enhances androgen receptor degradation which reduces invasion, but it lacks direct melanoma validation.	[55, 58, 82, 83, 84, 85, 86, 87]

4.1. Curcumin

Curcumin, the primary active compound in turmeric, exhibits anti‐inflammatory, antibacterial, antimicrobial and anti‐cancer effects both in vitro and in vivo [59, 60]. These anti‐cancer effects are achieved by inhibiting the growth of new blood vessels by tumours, as well as by halting tumour progression [60, 61]. Additionally, CUR presents with targeted cytotoxicity against malignant cell lines, such as in chronic lymphocytic leukaemia (B‐CLL) cells and multi‐drug resistant breast carcinoma cell line MCF7/TH, while exhibiting minimal impact on non‐cancerous cell lines [58]. Curcumin also blocks the harmful effects of mutagens and carcinogens and accomplishes this through its antioxidant effects, and neutralises free radicals, preventing harm to DNA [60]. It is hypothesised that these observed effects may also extend to melanoma.

In the context of melanoma treatment, CUR protects cells from damage due to UV radiation [60]. Despite its various potential therapeutic effects, the use of CUR is limited due to its low systemic bioavailability. Curcumin has low aqueous solubility, making it poorly absorbed, and thus metabolised and eliminated from the body [55]. Curcumin can influence various signalling pathways and molecular targets, highlighting its role as a multifunctional polyphenolic compound [59]. It has been shown to interact with β‐catenin, p38 MAPK, VEGF, and tumour necrosis factor‐alpha (TNF‐α), all of which play different key roles in melanoma development and progression [59]. In a study published by Kim et al., CUR decreased cytokines like TNF‐α, interleukin(IL)‐6 and ‐8, which exhibit pro‐tumour functions in melanoma. However, complete suppression of these cytokines can interfere with host immune responses, making treatment more challenging [62]. Combining CUR with immune checkpoint inhibitors like anti‐PD‐1 therapy may lead to opposing immunomodulatory effects. Curcumin aids in immune surveillance by the suppression of tumour cell PD‐L1 expression and depletion of immunosuppressive cells like regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs) [88, 89]. However, its potent anti‐inflammatory properties may inhibit key cytokines like IL‐6/8 risking the inhibition of dendritic‐ and T‐cell infiltration necessary for an immunotherapy response [88, 89]. Therefore, these findings may also apply to melanoma.

Furthermore, CUR has been shown to have a significant reduction in inducible PGE₂ [59]. In a study carried out by Sharma et al., a daily dose of CUR resulted in a 62% decrease in inducible PGE₂ production 1 h after treatment on day 1, and a 57% decrease 1 h after treatment on day 29, highlighting its reduced potency after prolonged use [90]. This holds significance in melanoma treatment as PGE₂ promotes immune suppression by inhibiting the activity of cytotoxic T cells and NK cells. A study performed by Dhillon et al. concluded that CUR reduces nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐ĸB), phosphorylated signal transducer and activator of transcription 3 (STAT3), and COX‐2, all of which play a role in inflammation that promotes tumour growth, tumour immune evasion and suppression, as well as cell growth and survival [64]. It is worth noting that these findings are derived from clinical trials involving patients with colorectal‐ and pancreatic cancer. It is anticipated that these findings will hold translational potential in melanoma.

Furthermore, according to research carried out by Lee et al. CUR decreased MMP‐2 and MMP‐9 expression, thereby minimising invasiveness in oral cancer [65]. Additionally, CUR elevated the expression of an EMT marker, E‐cadherin and a tumour suppressor gene p53 [65]. The key molecular targets implicated in melanoma progression and the influence of CUR on these targets are provided in Figure 1. Therefore, decreasing the activity of these transcription factors and enzymes would be favourable in terms of halting melanoma progression.

Figure 1.

Key molecular targets affected by CUR [91]. AP‐1, activator protein 1; Bcl‐2, B‐cell lymphoma‐2; Bcl‐x, B‐cell lymphoma‐extra‐large; CXCR‐4, C‐X‐C chemokine receptor type 4; HIF‐1, Hypoxia‐inducible factor 1; PDGF, platelet‐derived growth factor; TGF‐β1, Transforming growth factor beta 1. Adapted from Shanmugam et al. Image created using Biorender (https://BioRender.com).

4.2. Bisdemethoxycurcumin

Bisdemethoxycurcumin (BDMC) is a more stable curcuminoid and therefore, has the potential to enhance the effectiveness of cancer treatments [67]. Several studies have indicated that BDMC has an anti‐proliferative effect on various cancer cell lines, including breast, colon, glioma and leukaemia cells [67]. However, it is important to note that the biochemical basis of these effects remains under investigation. Bisdemethoxycurcumin does not react with oxygen on its own because it is devoid of both methoxy groups, as seen in the structure of BDMC (Figure 2) [67]. As reported by various studies, BDMC seems to be the most effective curcuminoid due to the increased stability conferred by its structure [67, 68, 69]. A study conducted by Lee et al., on an immortalised rat hepatic stellate cell line (HSC‐T6) revealed that BDMC decreases the levels of B‐cell lymphoma 2 (BCL‐2), leading to increased apoptosis. Additionally, BDMC increased reactive oxygen species (ROS) production, which resulted in DNA damage and subsequent cell death [65, 67]. Furthermore, BDMC has shown pro‐apoptotic effects in HSC‐T6 cells by interacting with cannabinoid receptor‐2 (CBR2), which leads to the activation of downstream targets like the Fas‐dependent death pathway, and caspases 3 and 8 [65, 67]. Lee et al., also found that inhibiting CBR2 decreased the apoptotic effect of BDMC [66] and by reducing the expression of CBR2 with small interference RNA a reduction in sensitivity to BDMC in liver cells was observed [66]. This suggests that BDMC exhibits apoptotic effects by interacting with CBR2. While Lee et al., observed this in hepatic cells, the high expression of CBR2 in malignant melanoma cells suggests that CBR2 is a robust therapeutic site. The binding of BDMC can lead to reduced cell growth, apoptosis and inhibition of metastasis by activating downstream effectors. Given that BDMC likely induces apoptosis through interaction with CBR2, non‐cancerous cells lacking this receptor are unlikely to be affected by the compound. However, it is important to note that these findings are extrapolated from cancer types other than melanoma, and it is anticipated that this curcuminoid will have similar effects in melanoma. The various molecular targets influenced by BDMC are illustrated in Figure 2 below.

Figure 2.

Key molecular targets affected by BDMC [67]. Bax, Bcl‐2‐associated X protein; NF‐kB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; ROS, reactive oxygen species; WIF‐1, Wnt inhibitory factor‐1. Image created using Biorender (https://BioRender.com).

4.3. Demethoxycurcumin

Demethoxycurcumin (DMC) has also proven to be more stable than CUR [70], which may be attributed to its chemical structure. Demethoxycurcumin lacks the methoxy group attached to the benzene ring, as illustrated in Figure 3, [70]. This curcuminoid has demonstrated promising anti‐cancer activities by interacting with multiple molecular targets in various cell lines, including brain, lung, ovarian, NMSCs and prostate cancer, prompting further research to determine its effectiveness in melanoma cell lines [70]. A study conducted by Jiao et al., revealed that ovarian cancer cells exposed to DMC led to the inactivation of the insulin receptor substrate 2 (IRS2)‐PI3K‐protein kinase B (Akt) pathway [71]. This holds promise in melanoma treatment as B16‐F10 murine melanoma cells express both insulin receptors (IRs) and insulin‐like growth factor 1 receptors (IGF‐1Rs) [70, 79, 80]. Therefore, the binding of insulin or insulin‐like growth factor 1 (IGF‐1) to their receptors triggers the phosphorylation of IRS2, which subsequently activates PI3K and its downstream targets [81]. However, DMC has shown to inhibit this binding and subsequent PI3K activation, resulting in decreased cell growth and metastasis [70, 71]. Ultimately, it is expected that these outcomes will be translated into melanoma.

Figure 3.

Key molecular targets affected by DMC [70]. ICAM‐1, Intercellular adhesion molecule‐1; MMP‐2, matrix metalloproteinase‐2. Image created using Biorender (https://BioRender.com).

Furthermore, DMC inhibited the invasion and metastasis of human breast cancer cells by decreasing the levels of MMP‐9, suggesting its usefulness in melanoma since MMP‐9 encourages cancer dissemination by degrading the ECM [70, 72]. In the same study by Yodkeeree et al., DMC suppressed the production of intercellular adhesion molecule‐1 (ICAM‐1) and C‐X‐C chemokine receptor type 4 (CXCR‐4) [70, 72]. This may contribute to the management of melanoma since ICAM‐1 plays a crucial role in cell‐cell and cell‐matrix interactions [73]. Activated CXCR‐4 aids in melanoma cell migration and invasion. Thus, targeting this receptor may offer a promising avenue for novel melanoma therapeutics [74].

Additionally, Wnt inhibitory factor‐1 (WIF‐1) expression is usually reduced in melanoma, resulting in uncontrolled Wnt signalling and increased cell proliferation and survival [75]. In a study performed by Liu et al., to determine the effects of DMC on A549 lung cancer cells, WIF‐1 expression was increased to baseline levels after treatment with 20 µM of DMC [70, 76]. Demethoxycurcumin upregulated WIF‐1 expression. Thus, its ability to act as a tumour suppressor, by demethylating the WIF‐1 promoter region, proves valuable [70, 76]. Moreover, DMC increased the rate of apoptosis in a prostate cancer cell line by upregulating caspase‐3, resulting in cell cycle arrest in the G₂/M phase [70, 77]. Prostate cancer cell migration and invasion were also reduced, and it is suspected that DMC influenced MMP‐2 activity [77].

Lastly, DMC led to cell cycle arrest in the G₂/M phase in human keratinocyte (HaCaT) cells [78]. This is a noteworthy observation since HaCaT cells are non‐tumorigenic. This suggests that although DMC shows promise as an anti‐cancer compound, it is essential to ensure that its effects on non‐cancerous cell lines are not excessively harmful, as that would undermine its therapeutic potential. The molecular targets mentioned above represent only a subset of those affected by DMC. Given the potential of DMC in treating various cancer cell lines, further investigation into its effects on melanoma cells is well justified. Figure 3 highlights key molecular targets influenced by DMC that are also involved in melanoma development and progression.

4.4. Dimethoxycurcumin

Dimethoxycurcumin (DiMC) is a synthetic analogue of CUR [58]. The chemical structure of DiMC differs from that of CUR, as it has four methoxy groups instead of two (Figure 4) [58] leading to increased stability. Overall DiMC seems to elicit a balanced anti‐/pro‐oxidant behaviour, which contributes to its enhanced potential as an anti‐cancer compound [58]. When reactive oxygen species (ROS) levels increase, it can lead to apoptosis, and DiMC has been found to increase ROS more rapidly than CUR without causing harm to non‐malignant cells [58, 82]. In addition to inducing apoptosis through ROS generation, DiMC has also been shown to trigger another form of programmed cell death known as paraptosis, further contributing to its selective cytotoxicity against malignant cells [58].

Figure 4.

Key molecular targets affected by DiMC. AP‐1, activator protein‐1; AR, androgen receptor; COX‐2, cyclooxygenase‐2; PGE₂: prostaglandin E2. Image created using Biorender (https://BioRender.com).

Paraptosis, a non‐apoptotic programmed cell death, aids in eliciting the malignant cell‐specific toxicity mechanism of DiMC, prompted by its ability to generate increased ROS in the form of mitochondrial superoxide and the inhibition of protein degradation [58, 83]. Unlike apoptosis, paraptosis results in swelling of the endoplasmic reticulum (ER) and mitochondria [83]. Research conducted by Yoon et al., indicated that DiMC triggers paraptosis in various resistant breast cancer cells, but not in non‐malignant breast cells, highlighting its ability to target malignant cells [58, 84]. Furthermore, in a study conducted by Lee et al., comparing the effects of CUR, BDMC, and DiMC on human renal carcinoma epithelial‐like Caki cells, DiMC caused the most significant reduction in cell viability by inducing apoptosis [85]. This further highlights the importance of methoxy groups in increasing the stability of these compounds and, therefore, potentially resulting in better therapeutic responses. Dimethoxycurcumin also led to the greatest increase in ROS production compared to CUR and BDMC [85]. Additionally, DiMC showed the greatest ability to trigger the release of cytochrome C, which subsequently activates caspase‐3, leading to apoptosis [85]. In another study by Pae et al., comparing the effects of CUR, BDMC, and DiMC on lipopolysaccharide‐activated RAW264.7 macrophages, DiMC was shown to be the most effective at inhibiting NF‐ĸB activity [86]. Additionally, DiMC inhibited COX‐2 expression, and halted PGE₂ production [86]. The effect of DiMC on the abovementioned molecular targets indicates its ability to exhibit various anti‐cancer effects, such as decreased proliferation, angiogenesis, and metastasis. However, it is important to note that not all these effects have been demonstrated in cancer cells. Dimethoxycurcumin also increased androgen receptor (AR) degradation in human renal cell lines [58]. This holds promise in melanoma treatment as ligand activation of the AR increases the invasion potential of melanoma [87]. Comparable to CUR, DiMC appears to interact with several molecular targets, and its increased stability due to its chemical structure highlights its potential role as a novel therapeutic option for melanoma. Lastly, it is worth emphasising that all the abovementioned effects on various molecular targets occurred in cancer types other than melanoma. It is anticipated that these effects would be translatable to melanoma. Figure 4 below illustrates key molecular targets influenced by DiMC. Furthermore, the various effects of curcuminoids and DiMC in preclinical models are described in Table 2.

Table 2.

Comparative anti‐tumour efficacy of curcuminoid derivatives and dimethoxycurcumin in preclinical cancer models.

Curcuminoid	Dose (μM)	Target and effect	Model (In vitro, in vivo)	Cell line/animal model	Tumour type specificity	Reference
Curcumin	20 μM	Decreased phosphorylation of AKT and mTOR	In vitro	U251 glioblastoma cells	Inferred from brain cancer	[92]
	10‐ and 20 μM	Increased PTEN expression	In vitro	U87 glioblastoma cells	Inferred from brain cancer	[92]
	20 μM	Suppressed p‐AKT and p‐mTOR expression while total AKT/mTOR levels remained unchanged	In vitro	NSCLC A549 lung cancer cells	Inferred from lung cancer	[93]
	10 μM	Inhibits proliferation and migration by downregulating VEGF/PI3K/AKT signalling and activating caspases‐3/‐8	In vitro and in vivo	HepG2 liver cancer cells	Inferred from liver cancer	[94]
	50 μM	Inhibition of tumorigenesis and angiogenesis	In vitro and in vivo	B16F1, B16F10, A375, SK‐Mel‐28, C57BL/6 mice	Melanoma specific	[95]
Bisdemethoxycurcumin	10‐80 μM	Impairs NSCLC cell viability by triggering apoptosis and autophagy via SMO/Gli1 downregulation	In vitro	NSCLC, A549, and 95D lung cancer cells	Inferred from non‐small cell lung cancer	[96]
	10‐, 20‐, 40‐, and 80 μM	Borneol synergistically enhances BDMC‐mediated G2/M phase arrest through ROS upregulation	In vitro	HepG2 liver cancer cells	Inferred from liver cancer	[97]
	5‐, 10‐, and 15 μM	Dose‐dependent treatment reduced SKOV‐3 growth and hindered attachment to Matrigel and fibronectin	In vitro	SKOV‐3 ovarian cancer cells	Inferred from ovarian cancer	[98]
	100 mg/kg/day	Inhibited tumour growth and reduced the proliferative capacity of malignant cells	In vivo	In vivo nude mice	Inferred from gastric adenocarcinoma	[99]
Demethoxycurcumin	12.5‐, 25‐, and 100 μg/mL	Bcl‐2 suppression which shifted cell cycle distribution from G1 to G2/M resulting in apoptotic cell death	In vitro	U87 glioblastoma cells	Inferred from brain cancer	[100]
	35 μM	Modulates the expression of DNA repair, cell cycle, and apoptotic pathway genes	In vitro	NCI‐H460 lung cancer cells	Inferred from lung cancer	[101]
	20 μM	Triggered WIF‐1 promoter demethylation	In vitro	A549 adenocarcinoma cells	Inferred from non‐small cell lung cancer	[76]
	20‐, 40‐, and 80 μM	Decreased cell viability and dose‐dependently triggered apoptosis	In vitro	SKOV‐3 ovarian cancer cells	Inferred from ovarian cancer	[102]
	Intravenous injections of 10‐ and 30 mg/kg DMC and 20 mg/kg TMZ	DMC and TMZ combination treatment inhibited glioma growth	In vivo	Nude mice implanted U251 and U87	Inferred from brain cancer	[103]
Dimethoxycurcumin	2.5–10 μM	Increased AR degradation and attenuated hypoxia‐induced VEGF expression via HIF‐2α downregulation	In vitro	Human renal cell lines	Inferred from renal cell carcinoma	[104]
	5–18 μM	Suppressed AP‐1 transcriptional activity while downregulating psoriasin and cyclin D1 expression	In vitro	HaCaT and HeLa cells	Inferred from keratinocytes and cervical cancer cells	[105]
	5–50 μM	Impaired the mitochondrial respiratory chain and ATP synthesis. Altered the cellular redox state (ROS/GSH), subsequently activating the p53 checkpoint to arrest in S‐phase	In vitro	MCF7 breast cancer cells	Inferred from breast cancer cells	[106]

5. Curcuminoid Delivery Systems

Although CUR offers various health benefits, its poor aqueous solubility, rapid degradation and metabolism constraints its clinical use. Existing literature supports using nanocarrier‐based drug delivery systems (NDS) to overcome the abovementioned hurdles [107]. Nanocarrier systems refer to nanostructured materials typically smaller than or equal to 1000 nm which are developed to enhance the solubility and bioavailability of hydrophobic compounds like curcuminoids [108]. Nanotechnology based delivery optimises the solubilisation profile of low solubility compounds [107, 109]. By promoting adhesive interactions between the nanocarrier and the intestinal mucosa, these systems prolong gastrointestinal transit and enhance the passive diffusion and active uptake of the therapeutic [107, 109, 110]. Nanocarrier delivery enhances the metabolic stability of encapsulated drugs by providing a barrier against the harsh gastrointestinal environment and therefore protects the compound from pH induced degradation [107, 111]. Lipid and polymer based nanocarriers have emerged as the primary strategies for overcoming the poor oral absorption of curcumin [107, 112]. However, a significant disparity remains between promising in vitro data and proven pharmacokinetic outcomes. It is important to note that increasing CUR bioavailability is not directly proportional its bioactivity. Future research should prioritise in vivo bioavailability and bioactivity studies to quantify the actual fraction of the dose of free unconjugated CUR that reaches the bloodstream. Table 3 summarises clinical evaluations in which NDS were tested in 12 healthy adult volunteers. The solid dispersion system using cellulose derivatives led to a 45.9‐fold increase in systemic exposure compared to free curcumin [113]. The solid dispersion technique shows such a significant increase because it transforms crystalline curcumin into a nanocrystalline form [113]. This lowers the energy barrier for dissolution in the gastrointestinal environment. Conversely, despite their efficacy in animal models, liposomal systems did not yield any significance in human trials [114]. In contrast, the use of phytosomes presents a moderate 12.7‐fold increase [113, 115]. Phytosomes remain a feasible option since its dependency on food grade lecithin ensures a robust safety profile and a cost effective, sustainable production process [113, 115]. Taking all of this into consideration, more research needs to be done to determine whether improved systemic exposure is directly related to increased anti‐melanoma efficacy.

Table 3.

Clinically validated delivery systems for enhanced curcumin bioavailability.

Delivery system	Primary carrier/matrix	Relative bioavailability versus free curcumin	Peak plasma concentration	Experimental subject group	Study reference
Solid dispersion	Polyvinyl pyrrolidone and cellulose derivatives	45.9‐fold higher	~ 2 h	Healthy volunteers	[114][115][113]
Phytosome	Soy lecithin and microcrystalline cellulose	8‐, 9‐ and 12.7‐fold higher	1–12h
Microemulsion	Micellar matrix	Significant increase	Faster than free CUR		[114]
Liposome	Phospholipids	Non‐significant	Similar to free CUR

6. Signalling Pathways Involved in Melanoma Progression

Various signalling pathways regulate gene expression, thereby facilitating processes associated with melanocyte proliferation and survival. As a result of these interactions, changes in these pathways can lead to uncontrolled signalling, giving rise to malignant disease [116]. An understanding of the mechanisms by which malignancies develop is crucial for research and the development of new treatments.

Firstly, the PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway is a central pathway implicated in various cellular processes, such as angiogenesis, apoptosis, and cell survival [116, 117]. Dysregulation of this pathway is common in several cancers, including melanoma [116]. Original non‐malignant melanomas, in the radial growth phase, progress to the more invasive vertical growth phase in approximately 70% of cases involving metastatic melanoma [116, 118]. The progression from the radial growth phase to the vertical growth phase is correlated with upregulated AKT activity [119]. A study conducted by Zhao et al., concluded that CUR reduced AKT/mTOR signalling in human melanoma cells [120]. Inhibition of this pathway led to autophagy in melanoma cells, resulting in a significant decrease in cell growth and invasion [120]. However, it is important to note that the effects of CUR may not be as potent in vivo due to its low systemic bioavailability. Furthermore, both DMC and DiMC have been shown to downregulate PI3K/AKT/mTOR activity in a variety of malignant cell lines, thereby decreasing cell survival, growth, migration, and metastasis [70, 79, 86]. Nonetheless, the effects of these compounds on melanoma progression specifically remain largely unknown.

An additional pathway frequently implicated in melanoma is the MAPK/ERK signalling cascade [121]. There are three groups of MAPKs, commonly referred to as ERKs, p38/SAPKs and c‐Jun N‐terminal kinases (JNKs) [122]. The latter two of the three MAPK groups mentioned are primarily involved in regulating the immune response, whereas MAPK/ERK signalling, largely triggered by growth factors, plays a fundamental role in cancer progression [121]. The mutations that activate the MAPK/ERK pathway are largely responsible for disease progression. In addition to these mutations, genetic and epigenetic alterations are the main drivers of reduced responsiveness to therapeutics [121]. Rat sarcoma (Ras) guanosine triphosphatases (GTPases), especially KRAS, NRAS and HRAS play a crucial role in disease development as these GTPases exhibit high mutation rates in solid tumours [121, 123]. These Ras‐GTPases, in turn, promote the accumulation of ARaf, BRaf and CRaf, which dimerise to activate kinase enzymes and subsequently phosphorylate proteins, such as mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK) [121, 124]. Over twenty BRAF mutations have been observed in melanoma, with BRAF^V600E in which valine is replaced with glutamic acid at position 600, being responsible for 80‐90% of BRAF mutations [121]. Additionally, this mutation has been identified in 60% of all melanomas of the skin [121, 125]. Curcumin and DiMC have been shown to downregulate MAPK/ERK activity, thereby decreasing cell growth, migration, and metastasis and increasing apoptosis [86, 126].

KIT mutations in melanoma result in uncontrolled cell growth and thus cancer progression [127]. The KIT gene produces c‐KIT protein known to control cell division. When KIT is mutated, the c‐KIT protein becomes overactive, resulting in uncontrolled proliferation [127]. KIT mutations can seldom occur along with BRAF or NRAS mutations, suggesting that these mutations could replace each other. These mutations activate similar pathways. Therefore, they rarely occur at the same time [127]. Since KIT mutations lead to the overactivation of the PI3K/AKT/mTOR and MAPK/ERK pathways, curcuminoids may counteract this by downregulating their activity.

Lastly, the wingless‐related integration site (Wnt)/Beta‐catenin (β‐catenin) pathway is also commonly involved in melanoma progression. Interestingly, gene mutations are not the main drivers of dysregulation of this pathway in melanoma [128]. Epigenetic alterations, such as promoter methylation of WNT inhibitory factor 1 (WIF‐1), silence this protein, leading to overactivation of the pathway [128]. This pathway plays a key role in the maturation of melanoma cells, and MITF is a critical gene implicated in this pathway. Increased β‐catenin levels lead to higher MITF levels, resulting in cells with a more elongated appearance but reduced invasiveness [128]. Furthermore, β‐catenin promotes the expression of BRN2, a key protein that regulates MITF levels, thereby affecting cell invasiveness [128]. However, administration of CUR, BDMC, and DMC has shown decreased activation of the Wnt/β‐catenin pathway, as these compounds upregulate WIF‐1 [75, 91, 129]. As a result, increased WIF‐1 levels halt melanoma progression by inhibiting the Wnt/β‐catenin pathway, thereby decreasing tumour growth and aggressiveness [75, 129].

Therefore, the disruption of the abovementioned signalling pathways drives uncontrolled cell growth through the activation of downstream transcription factors and permits local invasion and the spread to distant organs. Crosstalk between these pathways promotes phenotype switching, a reversible state change between a hyperproliferative‐ and invasive stem‐like state, which drives both initial and eventual resistance to MAPK/BRAF targeted therapies [130]. Natural curcuminoids as well as DiMC has the potential to halt these cancer progression pathways by inhibiting upstream MEK/ERK, PI3K/AKT phosphorylation and mTORC1 activation, and blocking β‐catenin. The effects of these curcuminoids and DiMC on the PI3K/AKT/mTOR and MAPK/ERK pathways are depicted below in Figure 5.

Figure 5.

Key components of the mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K) pathway affected by demethoxycurcumin (DMC), curcumin (CUR), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DiMC) [8, 131, 132, 133]. The blue arrow illustrates crosstalk between the MAPK and PI3K pathways. Phosphatidylinositol 3‐kinase can be activated by upstream receptor tyrosine kinases (RTKs), as well as by rat sarcoma virus‐guanosine triphosphate (Ras‐GTP) [134]. Standard black arrows indicate decreased activity, while blunt arrows show inhibition. Beige and green arrows denote steps that lead to activation. This pathway diagram has been adapted from data gathered in non‐melanoma cancer models, however most of these targets are implemented in melanoma. Image created using Biorender (https://BioRender.com). AKT, protein kinase B; BAD, Bcl‐2‐associated death promoter; ERK, extracellular signal‐regulated kinase; MEK, mitogen‐activated protein kinase kinase; mTORC1/2, mammalian target of rapamycin complex 1/2; P, phosphate; PDK1, phosphoinositide‐dependent protein kinase 1; PIP₂, phosphatidylinositol bisphosphate; PIP₃, phosphatidylinositol triphosphate; Raf, rapidly accelerated fibrosarcoma.

While these molecular insights establish curcumin as a promising phytochemical, several translational hurdles remain. The low bioavailability of curcuminoids along with the lack of robust clinical trials hinders clinical translation. Addressing these limitations requires a multidisciplinary approach in which collaboration among clinicians, chemists, and researchers is essential to overcome pharmacokinetic barriers.

7. Clinical Translation of Curcumin via Multidisciplinary Partnerships

A hallmark of curcumin's clinical profile is its safety and that it causes minimal side effects relative to standard chemotherapy treatments. Robust clinical trial data highlight its therapeutic efficacy across a broad spectrum of chronic conditions, including cancer [135]. Clinical trial data is highlighted in Table 4 below. According to clinicaltrial.gov and an extensive literature search no clinical trial data is currently available regarding the use of curcuminoids in melanoma patients. Notably, the use of CUR is limited because of its absorption and solubility leading to its lower bioavailability and bioactivity, but its therapeutic efficacy is not solely driven by the parent compound and can stem partly from its metabolites [136]. Findings imply that CUR is metabolised in the liver and converted into CUR conjugates [137, 138]. Since clinical and preclinical trials show curcumin's therapeutic efficacy despite its poor absorption, the observed therapeutic effects may be induced by its unmeasured metabolites. Although curcuminoids have undergone clinical evaluation for multiple malignancies, clinical trial data regarding their therapeutic use in melanoma remains scarce. Clinical trial data on colorectal cancer highlight that CUR shows promise in combating cancer. However, its use is limited due to its pharmacological constraints. Data suggests that CUR has an exceptional safety profile across a wide dosage range (360‐3 600 mg/day) improving patient health without causing harm [90]. On a molecular level, it demonstrated anticancer effects by suppressing PGE₂ and TNF‐α, reducing DNA damage, and triggering apoptosis via p53 and Bax upregulation [139]. Additionally, the use of CUR alongside standard colorectal cancer treatments successfully extended both overall and progression free survival [140]. Nevertheless, a key clinical limitation is its poor systemic bioavailability, as previously mentioned. The primary challenge concerning the therapeutic use of CUR is its failure to achieve sufficient biological activity in distant metastatic sites [141]. These findings are beneficial for melanoma treatment since it provides molecular data that CUR can disrupt key survival and apoptotic pathways. However, the successful clinical translation in melanoma heavily depends on overcoming bioavailability limitations. Therefore, future melanoma research should explore advanced drug delivery systems, and synthetic analogues like DiMC to bypass poor bioavailability. The successful clinical translation of CUR depends on a shift away from isolated discoveries in favour of partnerships among researchers, clinicians, and industry stakeholders. Curcumin offers a clinical advantage as an accessible, low‐toxicity phytochemical that holds potential in preventative and adjunct treatments. However, using this potential to its full capacity relies on overcoming its pharmacokinetic challenges through nanotechnology and improved drug delivery systems. Nevertheless, many drug delivery systems increase overall plasma levels of curcuminoids, but the predominant circulating forms are metabolites rather than free unconjugated curcuminoids. As such improved formulations can result in increased bioavailability, but this does not necessarily translate to increased therapeutic efficacy. Advancing Sustainable Development Goal 17 through multidisciplinary partnerships is essential for addressing these challenges, with collaboration among molecular researchers, chemists, and clinicians driving scientific innovation.

Table 4.

Clinical trials indicating the effects of curcumin in various cancer types.

Cancer type	Curcumin admixture	Cohort size	Administered amount	Treatment window	Observed effects	Reference
Breast cancer	San Huang decoction (Traditional Chinese Medicine combination)	30	10 g/day	1 day prior to and 7 days following surgery	A reduction in drainage of fluid, wound inflammation score, C‐reactive protein, IL‐6, IL‐8, and TNF‐α	[143]
Hepatocellular carcinoma	Curcuminoids + piperine + taurine	20	4 g + 40 mg + 500 mg	30 days	Decrease in IL10 and miR‐21	[144]
Multiple myeloma	Curcumin + melphalan + prednisone	33	8 g + 4 mg/m2 + 40 mg/m2	28 days	Decrease in NF‐kβ, VEGF, TNF‐α, and IL‐6	[145]
Oral malignancy	Curcumin	60	950 mg/day	3 months	Decrease in p53, Ki67, and cyclin D1	[146]
Pancreatic cancer	Curcumin	25	8 g/day	8 weeks	Increased IL‐6, IL‐8, IL‐10, IL‐1RA and decreased NF‐kβ, COX‐2, and p‐STAT3	[64]
Solid cancer tumours	Meriva (curcumin + lecithin)	80	180 mg/day	8 weeks	Decreased TNF‐β, TNF‐α, IL‐6, C‐reactive protein, substance P, calcitonin gene‐related peptide, and monocyte chemotactic protein‐1	[147]

Lastly, since CUR is compatible with sustainable extraction methods it poses as an eco‐friendly alternative to traditional synthetic drug synthesis, further justifying its development. Curcumin, is mainly produced via extraction from Curcuma longa or by chemical synthesis [142].

Given the promising therapeutic properties of CUR and its potential for mass production once approved for clinical use, it is also important to assess the environmental impact of its production. A study conducted by Zerazion et al., concluded that electricity use, especially the use of non‐renewable energy and its impact on global warming and air pollution, were the major contributors to environmental damage [142]. Of the three techniques applied, chemical synthesis of CUR was the least detrimental to the environment, as it yields the most CUR while producing the least waste [142]. Furthermore, analysis revealed that traditional extraction methods were the most harmful to the environment compared to chemical synthesis and microwave‐assisted extraction [142]. Future research should explore the long‐term use of CUR and evaluate curcuminoids in melanoma patient cohorts, as the literature currently lacks this information.

8. Conclusion

This review has compiled key properties of curcuminoids and a synthetic turmeric extract, dimethoxycurcumin, focusing on how these compounds influence various signalling pathways and their resulting impact on melanoma progression. However, it is important to note that curcuminoids may also exert harmful effects on non‐cancerous cells. Therefore, it is essential to evaluate their impact on both cancerous and non‐cancerous cell lines to determine whether they exhibit any cytotoxicity toward healthy cells. Furthermore, this review presents promising potential for the development of novel melanoma therapeutics, either as adjuvants to existing treatments or as individual options, given the shortcomings of current therapeutics. Although targeted and immune‐based therapies have greatly improved melanoma treatment, challenges such as therapeutic resistance, toxicity and high treatment costs remain concerning. Turmeric and its naturally derived curcuminoids, as well as the synthetic compound DiMC hold considerable promise in the treatment of metastatic melanoma. These compounds target various signalling molecules implicated in key pathways, such as MAPK and PI3K, that determine melanoma progression. Thus, by regulating these pathways, it could be advantageous in slowing disease progression and enhancing treatment approaches. Future research should investigate the combined effects of these compounds to assess the possibility of synergistic effects, as well as explore the exact molecular mechanisms by which these compounds exert their effects. Due to the low systemic bioavailability of curcuminoids, the use of carrier systems should be explored. However, certain analogues may possess superior stability or bioavailability despite lower in vitro cytotoxicity. Furthermore, the pharmacological profiles of natural curcuminoids versus their synthetic derivatives remain largely unknown, representing a gap in current melanoma research. Importantly, the anti‐melanoma potential of curcuminoids remains mostly preclinical, highlighting the need for dedicated translational validation. Due to the favourable safety profile associated with these compounds, they stand as potential candidates for further Phase I clinical trials. The role of primary health care screening in enhancing the effectiveness of melanoma treatment cannot be overlooked. Given that melanoma screening relies primarily on visual assessment, it does not require costly equipment but rather the proper training of primary health care workers. This makes it a practical and valuable intervention.

Author Contributions

Conceptualisation: Tivoli Visser, Charlise Basson, Priyesh Bipath and Yvette Nkondo Hlophe. Writing – original draft preparation: Tivoli Visser. Writing – review and editing: Tivoli Visser, Charlise Basson, Priyesh Bipath and Yvette Nkondo Hlophe. Funding acquisition: Yvette Nkondo Hlophe. Supervision: Charlise Basson, Priyesh Bipath and Yvette Nkondo Hlophe.

Ethics Statement

This study was approved by the Ethics Committee of the University of Pretoria (235/2025) and was conducted in accordance with the Declaration of Helsinki.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The authors have nothing to report.