Open access peer-reviewed chapter

The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma

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Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini

Submitted: 25 March 2022 Reviewed: 18 May 2022 Published: 24 June 2022

DOI: 10.5772/intechopen.105457

From the Edited Volume

Purinergic System

Edited by Margarete Dulce Bagatini

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Cutaneous melanoma is an aggressive and difficult-to-treat disease that has rapidly grown worldwide. The pharmacotherapy available in so many cases results in low response and undesirable side effects, which impair the life quality of those affected. Several studies have been shown that the purinergic system is involved in cancer context, such as in cutaneous melanoma. With technological advances, several bioactive compounds from nature are studied and presented as promising adjuvant therapies against cancer, as phenolic compounds and related action by purinergic system modulations. Thus, phenolic compounds such as rosmarinic acid, resveratrol, tannic acid, as well as vitamin D may be promising substances in a therapeutic perspective to treat cutaneous melanoma via purinergic system pathway. More research needs to be done to open up new horizons in the treatment of melanoma by the purinergic signaling.


  • purinergic signaling
  • skin cancer
  • adjuvant therapies
  • therapeutic target

1. Introduction

Cutaneous melanoma (CM) is a disease that arises in transition of dermis and epidermis, where the melanocytes are localized. The melanogenesis process starts due to DNA damage secondary to a UV exposition, which can be chronic or acute intermittent exposure. Furthermore, other risk factors are associated with melanoma as frequency of sunbathing, ultraviolet A exposure, low skin phototypes, atypical nevus syndrome, skin sunburn events mostly during childhood and adolescence, a large number of skin moles (congenital or not), familiar or personal history of CM or skin cancer not melanoma. The DNA damage alters the proliferation and cell cycle, culmining in dysregulated apoptosis mechanisms. The CM is characterized by the high invasiveness, a high metastatic capacity, causing a short survival period and high mortality rates due to pharmacological resistance [1, 2].

For the systemic treatment of the patient with high-risk disease to metastasis, pharmacotherapy is used with drugs that can manifest collateral effects, in addition to presenting inefficient mechanisms to guarantee the survival of patients [3]. In this sense, several literatures have indicated biochemical therapy as a promising adjuvant in the CM management [4], even so it is urgent researchers to develop new options for a rise in patients’ survival [1]. Therefore, many research science teams have been engaged to discover melanoma treatment and an interesting alternative to this would be to use natural substances, such as phenolic compounds that can have anticancer effects [5].

An efficient and rapid diagnosis is a priority among the medical and scientific community [6]. Furthermore, correctly and effectively pharmacological therapy promotes better prognosis and better quality of life for the melanoma cutaneous illness. Taking into consideration, the aim of this chapter was to provide an overview of potential modulations of the purinergic system in the treatment of cutaneous melanoma. Thus, initially, the cutaneous melanoma will be characterized based on epidemiology and therapeutics, as well as the purinergic system with its details, and finally, show that some natural compounds have potential in modulating purinergic signaling in melanoma.


2. Cutaneous melanoma: Epidemiology and current therapeutic treatments

Cutaneous melanoma is a disease that has a wide spectrum in relation to the prognosis of the patient who develops this disease. The diagnosis can be made from when the neoplasm is still restricted to the epidermis (in situ) in the disseminated form, where the malignant disease can affect other organs [7]. Data from the latest Global Cancer Statistics survey estimated for the year 2020 that cutaneous melanoma represents 1.7% of all malignant neoplasms, corresponding to 324,635 new cases worldwide. The number of deaths due to melanoma was 57,043. Comparing these numbers with the previous survey (2018), there was a considerable increase in the number of new cases, which was 232,100, as well as the number of deaths recorded (55,550 deaths). Both incidence and mortality rates differ according to each region of the planet, in addition to regions within the same country. Oceania has the highest ratio of number of cases; in Australia for the year 2020, it was expected 1 case of melanoma for every 104 male inhabitants and 1 case for every 185 females [8].

Also, North America and some European countries have high incidence rates of this disease. In the United States alone, 99,780 new cases and 7650 deaths from melanoma are expected in 2022 [9]. In the Scandinavian region, the incidence ranges from 15 to 18 cases/100,000 inhabitants; Northern European countries vary from 12 to 28 cases/100,000 inhabitants [10]. In Asia, Africa, and South America, the number of cases is lower, although there are regional differences as is the case in Brazil, where the South and Southeast regions have the highest number of cases when compared with other areas of the country [11, 12, 13, 14].

Early detection of cutaneous melanoma is a fundamental factor in reducing mortality. Individuals diagnosed in the early stages have a 98% survival rate, while those diagnosed in advanced stages have a significantly decreased survival rate—between 63.8 and 15%. Patients diagnosed with stage III and IV melanoma have survival rates (5 years) of 70% and 30%, respectively. For most human malignancies, the use of chemotherapy for systemic treatment changed the natural history of the disease, and in melanoma the reality, until recently, was different with response rates comparable to the use of placebo [15]. Since the introduction of chemotherapy for adjuvant treatment of malignant neoplasms, numerous therapeutic regimens have been tried in patients with metastatic melanoma [16, 17].

The most widely used treatment for patients with disseminated disease was dacarbazine, but only about 15–20% had some degree of response and 2% were still alive after 5 years of follow-up: a response rate comparable to the placebo-treated group of patients in the early clinical trials [15]. The use of high-dose interleukin-2 (IL-2) was the first treatment that changed the natural history of a small portion of patients with stage IV melanoma, but resulted in severe side effects that often affected survival [18, 19]. In the following years, molecules with direct action on pathways were responsible for controlling cell growth and division emerged, which were called “targeted therapy,” such as BRAF and MEK inhibitors [19, 20]. However, only part of the melanoma patients can benefit from these inhibitors, because it is necessary that the genes involved in these pathways are mutated in order to get a response [21].

With the development of immunotherapy, other molecules called “immune system checkpoint inhibitors”, such as pembrolizumab and nivolumab (programmed cell death protein-1 [PD-1] inhibitors), and ipilimumab (cytotoxic T lymphocyte antigen-4 [CTLA-4] inhibitor), have been routinely used as adjuvant and neoadjuvant treatments in melanoma patients with prognostic factors associated with poor survival [22, 23]. However, only 20% of patients show complete and lasting response with this type of therapy, and no biomarkers have been defined yet that can predict who will benefit from the use of these drugs [23, 24, 25].


3. Evidences that purinergic system plays a role in cutaneous melanoma

The purinergic system is a sophisticated cell-cell communication and ubiquitously expressed in the human body that orchestrates numerous cellular responses in the context of health and disease, displaying several biological processes. Most discussed extracellular signaling molecules include nucleotides such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and the nucleoside adenosine (Ado) [26, 27, 28, 29, 30]. The components belonging to this system are divided between receptors, according to the signaling molecule, as well as in enzymes. Thus, the P2 receptor is sensitized by adenine nucleotides, such as ATP, ADP, and AMP, being subdivided into P2X (1–7) and P2Y (1–12), while the P1 group is signaled Ado molecules and differentiated into A1, A2, A2B, A3 [31]. The levels of signaling molecules are controlled by enzymes known as ectonucleotidases, expressed on the surface of cells. They are nucleoside triphosphate diphosphohydrolase 1 (NTPDase-1/CD39), 5′-nucleotidase (5’-NT/CD73), and adenosine deaminase (ADA) enzymes, which metabolize ATP/ADP into AMP, AMP into adenosine (Ado), and finally this into inosine, respectively [32, 33, 34, 35] (Figure 1).

Figure 1.

Purinergic system components and functions. Adenosine triphosphate (ATP), key molecule of the purinergic system, can be released in an extra-cell environment and act as agonist on P2XR and P2YR. Furthermore, the ectonucleotidases presenting on cell surface are capable to hydrolyze the ATP into others nucleotides, such as adenosine monophosphate (AMP), adenosine diphosphate (ADP), and nucleosides, such as adenosine (ado). Between the purinergic receptors, only P1 (P1R) have Ado as agonist. The ectonucleotidase pyrophosphatase/phosphodiesterase (E-NPPS) has potential to break ATP straight to AMP, whereas ectonucleoside triphosphate diphosphohydrolase (E-NTPDase-CD39) can break ATP to ADP or ADP to AMP. In this enzyme orchestra, only one ectoenzyme is capable of hydrolyzing AMP to Ado, the ecto-5′-nucleotidase (E-5’-NT-CD73). In the end of the purinergic cascade, the adenosine deaminase (ADA) converts Ado to inosine (Ino). Source: The authors (2022).

In this context, it is well known that this system is involved in cancer dynamics and has a close relationship with the immune responses, such as in lung cancer [36, 37], leukemia [38], cutaneous melanoma [30, 39], pancreatic cancer [40], and gastric cancer [41]. Likewise, it has been reported that ATP is considered a pivotal molecule, which largely influences immune responses in peripheral and central tissues, can be released from the inflammatory and tumor cells via different mechanisms, such as exocytosis, plasma-membrane channels pannexin, or lysis, and getting accumulated in tumor microenvironment (TME) [42, 43, 44, 45, 46].

Thus, yet few studies have been performed to understand the involvement of purinergic signaling in melanoma, some robust evidence showed that this cell pathway plays an important role in this disease. In this sense, a component-system widely reported is the P2X7 receptor, which is expressed by cancer cells, as in melanoma, and is mostly associated with tumor cell killing via ATP key molecule signaling modulation [47, 48, 49]. However, if hydrolyzed to ADP can present an immunosuppression effect [39], as well as Ado, a nucleoside product of ATP hydrolysis that mediates the protective response, such as immunosuppressive and anti-inflammatory effects on healthy tissues, has a pro-carcinogenic property on melanoma [50, 51, 52, 53]. Data about the role of ATP in melanoma patients were found by Mânica et al. [50], who indicated that an increased inflammatory process by extracellular ATP leads to an immunosuppressive profile even after surgical removal, which, in turn, corroborated previous information.

Given the pleiotropic actions, the role of P2X7R depends on the nucleotide receptor-interactions, as well as concentration, being that these interactions can promote or inhibit melanoma. Taking account, recently it was reinforced that P2X7 is overexpressed in patients affected by metastatic malignant melanoma and that its expression closely correlates with reduced overall survival. This is because P2X7 stimulation is capable of miRNA-containing microvesicles and exosomes from melanoma cells [54]. Furthermore, it was hypothesized that the Warburg effect is possibly linked to P2X7 modulation by ATP in melanoma. Once activated by ATP, the PI3K-AKT pathway upregulates glycolytic cascade enzymes, which promotes lactate generation and acidification of the TME. Acidification of extracellular microenvironment alters immune response and supporting cancer [5].

Conversely, Hattori et al. [55] by treatment of B16 melanoma cells with oxidized ATP (oxATP) found significantly decreased cell proliferation at concentrations between 300 and 500 mM in low pH conditions. From this, they proposed that the P2X7R is a promising target for treatment of solid tumors. The same way, White et al. [56] after an experimental incubation of melanoma cells with P2X7-agonist 2′–3′-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate found decrease in cell number. In the immunological scenario, P2X7 activity has been associated with tumor-infiltrating T cells (TILs), which leads to senescence and limits tumor suppression, in addition to affected cell cycling of effector T cells and resulting in generation of mitochondrial reactive oxygen species (ROS) and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A [57].

Although the P2X are widely related, other receptors also have been involved in melanoma disease. The P2Y1 receptor was indicated as potential to reduce melanoma cell proliferation; however, P2Y2 usually appears to increase cell numbers [58]. Still, the P2Y12 seems to promote tumor metastasis by platelet activation in melanoma cells [59, 60]. Interestingly, one factor, which leads to skin cancer, UV-B irradiation, seems to have a relationship with purinergic signaling, and severe effects have been associated between irradiation type and reduced P2X1 and P2Y2 receptors, as well as to destruction of P2X7 receptors, with the possibility of contributing to malignant transformation of keratinocytes [61].

From the Ado-stimulated receptor perspective, the A2AR and A3AR seem to lead to melanoma cells’ death via proliferation mechanisms. Deletion of A2ARs was capable of reverting immunosuppression in B16-melanoma-bearing mice, immune cells responses [62, 63, 64]. Koszałka et al. [65] also showed that A1R, A2AR, and A3R receptors play an important role in melanoma (B16 type cells) by modulating angiosupport and immunosuppression in mice. An interesting study performed with melanoma cells discovered that A2B receptor blockade can impair IL-8 production, whereas blocking A3 receptors, it is possible to further decrease VEGF secretion in melanoma cells treated with etoposide (VP-16) and doxorubicin. Thus, treatment of melanoma cells with the DNA-damaging drugs such as VP-16 and doxorubicin resulted in Ado receptors modulations and chemotherapeutic potential [66].

On the other side, ectonucleotidases that control the purinergic chain also are involved in neoplasias. The CD39 decreased activity mitigates ATP hydrolysis, leading to extracellular accumulation of this nucleotide. This was evidenced by Manica et al. [50] that showed that post-surgery CM patients present high ATP levels in microenvironment compared with the healthy controls, suggesting being the cause of poor prognosis [50]. Thus, the ectonucleotidases action seems to play an important role in cancer context as well as in other purinergic components.

Although the CD39 and CD73 dynamics are responsible for forming most Ado extracellular content, another enzyme involved is the E-NPP, which hydrolyzes AMP to Ado. Several studies have evidenced that these ectoenzymes are increased in cancer context [45, 67, 68, 69]. In melanoma, studies suggested high expression of the CD73 in patients [70, 71, 72]. Also, in the melanoma mouse model, a CD73 inhibitor improved T and B cell-mediated antitumor immunity and reduced tumor growth [73]. The hydrolysis CD73 capacity is known and involved in melanoma; however, recently a nonenzymatic action of this enzyme was related, playing a role in cell migration on extracellular matrix through focal adhesion kinase (FAK) [74].


4. Natural compounds with antitumor effect and their purinergic system relationship

Considering the need for new therapies and therapeutic targets for the treatment of cutaneous melanoma, studies with compounds that modulate the purinergic system and have antitumor effects have been carried out, as is the case with phenolic compounds and vitamin D [75, 76]. Figure 2 represents some possible modulatory mechanisms of natural compounds on the purinergic system in the CM context.

Figure 2.

Purinergic system modulation in cutaneous melanoma by means of natural compounds. The literature has been evidenced in the adjuvant therapeutic perspective that several compounds derived from nature can act against carcinogenesis and cutaneous melanoma. Resveratrol, from the grape, has the potential both to increase CD73 expression and modulate P2X7 receptors, which control the growth progression and metastasis. Rosmarinic acid, a phenolic acid from rosemary, can block the P2X7 receptor and inhibits the agonist mechanism by ATP, as well as have antagonism ADP-like on the P2Y12 receptor, leading to a decrease of tumor mass formation. Two important derivatives of coffee, the caffeic acid and caffeine, have been shown as interesting modulators of P1 receptors. These adenosinergic receptors are intimately related to tumor immunity, and these two molecules can act modulating the antitumor immunity. The vitamin D also showed a significant compound with purinergic system modulation, since it is capable of increasing CD73 expression and controlling the adenosine amount, which seems to play a great role in cutaneous melanoma. Source: The authors (2022).

Phenolic compounds are secondary metabolites present in plants, whose function is to participate in their development and protect them from pathogens and UV radiation [77]. More than 8000 compounds have been identified so far, and most of these compounds have some beneficial property to humans [78]. Their therapeutic actions are related to the structure, mainly to the phenolic rings, in which these compounds are classified by the number of rings and structural elements they have, forming four major groups: phenolic acids, stilbenes, lignans, and flavonoids [79]. The most cited group of polyphenols in the literature with therapeutic actions including antitumor effect is flavonoids, which are present in foods consumed daily such as fruits, vegetables, vegetables, red wine, coffee, and green tea [80, 81, 82].

Resveratrol (3,5,4-trihydroxy-trans-stilbene) is found in red wine and in the skin of dark grapes, a polyphenol with antitumor activity, considered a candidate for the treatment of cutaneous melanoma, which has been shown to modulate the expression and activity of CD73, ADA enzyme, and P2X7 and A2A receptors, which are closely related to tumor progression [83, 84, 85, 86]. Tannic acid, a polyphenol, was shown to be able to induce cell death in several types of cancer cells, such as cutaneous melanoma, prostate cancer, glioblastoma [87, 88].

Thus, Bona et al. [89] tested the antitumor effect of this substance in rats with glioblastoma and the interference with ectonucleotidases, in which tannic acid was able to increase the hydrolysis of ATP and AMP nucleotides and decrease the hydrolysis of ADP in platelets of the animals treated compared with untreated. In the lymphocytes of the animals with the disease that received tannic acid, this polyphenol decreased the hydrolysis of ATP and ADP and the degradation of adenosine in relation to the group with the disease that did not receive the substance. When comparing the levels of ectonucleotidases in control mice, those with glioblastoma and those with glioblastoma treated with tannic acid, it was observed that the substance was able to maintain levels similar to those in mice without the disease. Bearing in mind that the purinergic system is able to modulate tumor progression, the aggressiveness of this type of cancer, and the results obtained in the study in question, tannic acid can be considered a promising agent for the treatment of cancer [89].

Regarding purinergic system modulation and the antitumor effect on cutaneous melanoma, Silva et al. [5] proposed the hypothesis that rosmarinic acid, a polyphenol with antitumor effect, would be able to modulate purinergic signaling and prevent tumor progression and metastasis by two-way means: by blocking the P2X7 receptor or by antagonizing the P2Y12 receptor. Interestingly, a paper that focused on Salvia yunnanensis extract, which contains rosmarinic acid in its composition, proved the inhibition ADP-induced of rabbit platelet aggregation by binding rosmarinic acid with P2Y12R [90].

Coffee (Coffea arabica) and green tea (Camellia sinensis) derivatives such as caffeine (1,3,7 trymetylxantine), caffeic acid (3,4-dihydroxycinnamic acid) and chlorogenic acid (3-O-caffeoylquinic acid) have shown promising effects in degenerative and cardiovascular diseases, in which they have been shown to modulate inflammation and purinergic signaling, mainly through the P1 family receptors that are closely related to tumor immunity, being strong candidates for the treatment of CM [91, 92]. To confirm the previous data, caffeic acid together with the antineoplastic dacarbazine decreased the viability of SK-Mel-28 metastatic cutaneous melanoma cells [93].

Quercetin, an abundant flavonoid in plants, also demonstrated antitumor activity in cell lines of bladder cancer, glioblastoma, and hepatocarcinoma and inhibited the activity and expression of ecto-5′- NT/CD73, leaving less Ado available in the TME, consequently preventing immunosuppression [94, 95, 96].

Apigenin (4′,5,7-trihydroxyflavone) is a flavonoid present in significant amounts in parsley, onion, celery, orange, chamomile, oregano, and basil that has shown a beneficial effect in diseases such as cancer, Alzheimer’s, diabetes, and depression [97, 98]. Cutaneous melanoma cells (A375) were treated with these substance and, in addition to the decrease in cell viability, they had an increase in ATPase activity and a concomitant reduction in the ATP/ADP ratio related to the apoptotic process of cancer cells, demonstrating that the present substance has an effect antitumor in addition to acting in purinergic system [99].

The carcinogenesis can be initiated by the overproduction of reactive oxygen species (ROS), since the antioxidant defenses cannot neutralize these molecules. From this, the antioxidant compounds seem to be important against tumor formation, such as the phenolic acids, which can prevent DNA alterations and genome instability. The literature has shown that rosmarinic acid is an example of a powerful antioxidant for the protection of the DNA against UV and H2O2 [100].

Vitamin D, in turn, is a fat-soluble vitamin, in which its deficiency is closely related to carcinogenesis [101]. This vitamin is available in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), where it can be obtained through the diet, but 90% of the daily needs are produced by the skin itself and later must be hydroxylated by the liver and kidneys, in order to obtain 1,25-dihydroxyvitamin D, the metabolically active form of vitamin D [102]. In metastatic melanoma cells, SK-Mel-28-treated with 1,25-dihydroxyvitamin D, there was decrease in cell viability, as well as the expression and activity of the CD73 enzyme and the levels of Ado, which has a suppressive function of tumor immunity and is essential for progression tumor, becoming a promising candidate for the adjuvant treatment of cutaneous melanoma [103].


5. Conclusion

As evidenced, cutaneous melanoma is a malignant neoplasm of great medical importance due to high rates of resistance to treatments and relapses, and for this reason, it is necessary to search for new and effective pharmacological therapies. In this context, the potential of some compounds in modulations of this pathway signaling, such as rosmarinic acid, resveratrol, tannic acid, as well as vitamin D, has been elucidated in this study. Of course, more research needs to be done to open up new horizons in the treatment of melanoma by the purinergic signaling, but the discovery of new ways to improve the anticancer pharmacological perspective has already begun.


Conflict of interest

The authors declare that there is no conflict of interest.



MDB acknowledges grant support by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, proj. No 310606/2021–7) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC, proj. No 2021TR1543). GBS, DM, MM, and MDB also thank Fundo de Apoio à Manutenção e ao Desenvolvimento da Educação Superior (FUMDES/UNIEDU) for the graduate scholarships.


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Written By

Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini

Submitted: 25 March 2022 Reviewed: 18 May 2022 Published: 24 June 2022