Studies on cbd oil for melanoma

Roles of Cannabinoids in Melanoma: Evidence from In Vivo Studies

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Abstract

Melanoma is the fourth most common type of cancer diagnosed in Australians after breast, prostate, and colorectal cancers. While there has been substantial progress in the treatment of cancer in general, malignant melanoma, in particular, is resistant to existing medical therapies requiring an urgent need to develop effective treatments with lesser side effects. Several studies have shown that “cannabinoids”, the major compounds of the Cannabis sativa L. plant, can reduce cell proliferation and induce apoptosis in melanoma cells. Despite prohibited use of Cannabis in most parts of the world, in recent years there have been renewed interests in exploiting the beneficial health effects of the Cannabis plant-derived compounds. Therefore, the aim of this study was in the first instance to review the evidence from in vivo studies on the effects of cannabinoids on melanoma. Systematic searches were carried out in PubMed, Embase, Scopus, and ProQuest Central databases for relevant articles published from inception. From a total of 622 potential studies, six in vivo studies assessing the use of cannabinoids for treatment of melanoma were deemed eligible for the final analysis. The findings revealed cannabinoids, individually or combined, reduced tumor growth and promoted apoptosis and autophagy in melanoma cells. Further preclinical and animal studies are required to determine the underlying mechanisms of cannabinoids-mediated inhibition of cancer-signaling pathways. Well-structured, randomized clinical studies on cannabinoid use in melanoma patients would also be required prior to cannabinoids becoming a viable and recognized therapeutic option for melanoma treatment in patients.

1. Introduction

The history of humans and pathogens combat back to many years ago. Some other diseases, such as different types of cancers including melanoma, later emerged, and are mostly related to human genetics backgrounds and one’s lifestyle. However, it is quite difficult to say who the winner is; nobody can ignore the crucial role of traditional medicine and modern medicine in overcoming the disease’s attack. Regardless of accessibility, availability, and affordability, both have saved millions of lives. However, it can be said that herbal medicine has been associated with life since the beginning of human existence. Traditional medicine is defined as the sum total of the knowledge, skills, and practices indigenous to different cultures, used in the maintenance of health, as well as in the prevention, diagnosis, improvement, or treatment of physical and mental illness (World Health Organization). In this way, medicinal herbs as fresh or dried raw materials composed of crude raw plant material, standardized plant extracts, and isolated pure compound molecules are the basic pillar of traditional medicine [1].

The use of natural materials originating from medicinal herbs and replacing synthetic chemicals with these natural products is one of the most important needs of today’s civilization, especially in developing countries [2]. Among 35,000–70,000 medicinal plant species, some are more famous for cancers. There is a growing number of articles that explore the importance of compounds called “cannabinoids” exclusively found in cannabis plants, which can reduce cell proliferation and induce apoptosis in melanoma cells.

Melanoma is a highly metastatic skin cancer whose global incidence and mortality continues to rise, with about 80% of skin cancer-related deaths associated with melanoma [3]. In 2018, approximately 278,723 new cases of melanoma resulting in an estimated 60,712 deaths were reported in 46 countries [4]. The incidence and mortality rates were higher in males (150,698 and 34,831, respectively) than in females (137,025 and 25,881, respectively) in these countries [4]. According to the Australian Institute of Health and Welfare, as of 2019, melanoma is the third most common cancer in both females and males, with an incidence rate that is even higher than that of lung cancer. A recent study analyzed the standardized data on melanoma incidence rates (up to 2015) in susceptible populations in Canada, the United States of America, Australia, Denmark, Sweden, Norway, the United Kingdom, and New Zealand [5]. This study showed that Australia had the highest rate of occurrence, with 50.3 people for every 100,000 people, followed by New Zealand (47.4 in every 100,000), Denmark (32.7 in every 100,000), and Canada (17.9 in every 100,000) had the lowest incidence rate [5]. Further analysis according to the Australian Institute of Health and Welfare showed that as of 2019, the estimated number of new cases and death was 15,229 and 1725 in melanoma, respectively, which was higher than those from previous years. This data indicate that melanoma is a significant health risk in Australia. The main factors associated with the development of melanoma include exposure to UV rays [6], age, and male gender [7], individuals with a family history of skin cancer [8], and poor immune function or rare genetic abnormalities [9].

For more than three decades, the major chemotherapeutic agents for melanoma therapy have been combination of cisplatin and 5- fluorouracil which act selectively, promoting apoptosis by interfering with DNA synthesis in actively dividing cancer cells [10]. Later on, a cytostatic alkylating agent was introduced as a standard option for chemotherapy in clinical management of melanoma [11]. Temozolomide and dacarbazine were used in particular for treatment of early non-metastatic melanoma, but the general success was very limited for metastatic melanoma [12]. Numerous mutant BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitors have been developed to target these mutant proteins. Originally, the most effective inhibitor was PLX4032 (also known as vemurafenib) with a 69% response rate in phase 1 clinical trials [13,14]. Preclinical studies further showed that antibodies against CTLA4 (T-lymphocyte-associated protein 4) induced regression of some murine tumors. As a result, currently two CTLA4 blocking monoclonal antibodies have entered pivotal clinical trial testing [15]. Ipilimumab (MDX010) is an antibody that targets human CLTA4 protein, and enhances T-cell activation and proliferation including the tumor-infiltration T-effector cells [16]. Tremelimumab is another antibody inhibitor for CTLA4 by 6.6% response rate in phase II of trial testing in metastatic melanoma [17]. Nivolumab is a human monoclonal antibody that antagonizes the programmed cell death protein-1 (PD-1) and PD-2 by blocking their receptors [18]. Thus, antibodies targeting CTLA4 and the PD-1 appear particularly effective targeted immunotherapies for melanoma and as the underlying mechanisms are unraveled, these inhibitors may be combined with alternative drugs such as cannabinoids to improve anti-tumor immune responses of patients with advanced melanoma or those responding to the current therapies.

The efficacy of all these conventional melanoma therapies such as surgical resection, chemotherapy, and immunotherapy is limited due to the high metastatic rate of melanoma and multiple resistance mechanisms coupled with substantial undesirable side effects of some of these therapies [19]. Developing new methods and therapeutic strategies to treat this aggressive cancer is therefore critical. The human skin has the endocannabinoid system composed of enzymes, receptors, and ligands which regulates skin homeostasis including the release of inflammatory compounds, cell differentiation, and division [20]. This system does have receptors for multiple compounds, including those derived from plants such as cannabis/hemp.

Cannabinoids are important compounds exclusively derived from the plant Cannabis sativa L. which could be potential agents for the treatment of melanoma. There are more than 120 known phytocannabinoids that can be found from Cannabis sativa L., cannabidiol (CBD) and tetrahydrocannabinol (THC) are the most abundant cannabinoids originating from cannabis. Both of these cannabinoids act together with the cannabinoids system and cause various natural effects [21]. Tetrahydrocannabinol (THC) can bind to receptors in the endocannabinoid system, helping to regulate cell division and potentially inhibiting or killing melanoma [22]. Therefore, cannabinoids have been used as therapeutic agents for several human and animal disorders including cancer [23,24,25].

The use of cannabis has always been very controversial because it is classified as an illegal drug due to THC. Despite this classification, there has been an increased scientific interest in recent years of the potential use of cannabis derivatives in medical applications [26]. Review of recent work has indicated that targeting the endocannabinoid system with cannabinoids can reduce the growth of breast, colon, liver, and prostate cancer [22,27]. Cannabinoids have also been used to successfully treat cancer cachexia, increasing the appetite of cancer patients; however, the associated side effects unfortunately adversely affected the patients’ quality of life [28]. Cannabinoids do not just stimulate appetites in some patients but have also been used to reduce pain and nausea in cancer patients [27].

Medical cannabis and its derivatives can selectively target tumor cells without exerting a cytotoxic effect on healthy cells [29]. This is its main benefit compared to chemotherapeutic agents which also affect cancerous tissues [30]. Extracts from Cannabis sativa L. have the potential not only to enhance survival rates but also to potentially improve the quality of life in melanoma patients [31]. While a great number of in vitro studies [32] (see Glodde et al. (2015)) have provided evidence of positive outcomes on using cannabinoids for treating melanoma cells, there are few in vivo and clinical studies that have been published [33,34].

The mechanism of cannabinoid action is associated with G-protein coupling with cannabinoid receptors CB1 and CB2. The CB1 receptor is present mostly in the brain or on the membrane of nerve cells. It is believed that the psycho-activity triggered by cannabinoids is largely controlled by this receptor. CB2 receptors are expressed only in immune cells, such as T and B lymphocytes and macrophage [35]. Through these interactions, cannabinoids regulate the signaling pathways involved in cell division, inhibiting division or metastasis of cancer cells, enhancing autophagy, and inducing apoptosis [36,37].

In this study, we searched in different databases such as SCOPUS, EMBASE, ProQuest Central, and PubMed from inception. Of the 622 screened studies, six studies with were included which matched our criteria. We assessed whether cannabinoid use was effective for treating melanoma by investigating tumor growth, inhibition of metastasis, and quality of life and movement. The finding from this systematic review should show whether cannabinoids have been effective for melanoma treatment, and provide a basis for its clinical use.

2. Methods

2.1. Inclusion Criteria

In this review, the inclusion criteria for relevant studies were:

The study should be a primary research article;

The study should include the use of cannabinoids (endocannabinoid, phytocannabinoids, and synthetic);

Cannabinoids should have been used in treating melanoma;

In vivo studies that explored the effect of cannabinoids on tumor activity or size were selected;

All study types were included except reviews and commentaries.

2.2. Exclusion Criteria

The exclusion criteria were:

The article was not written in English;

It was a judgement article;

The reported study was not on animals;

The article or study was not related to melanoma;

The article was not related to cannabinoids.

2.3. Search Strategy for Identification of Studies

In this review, the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines and checklist were followed [38]. Comprehensive literature searches were conducted using the EMBASE, SCOPUS, ProQuest Central, and PUBMED databases. The first step involved using “cannabis” and “cannabis-related”, “melanoma”, “in vivo”, or “animal” as search terms. A combination of these key terms was used to generate other search terms such as Cannabinoids* OR “Cannabis sativa” OR Tetrahydrocannabinol OR “THC” OR cannabidiol OR CBD OR “cannabidiol acid“ OR CBDC OR cannabigerol OR CBG OR “cannabis chromene” OR CBC OR anandamide OR AEA OR “endocannabinoids” OR “2-AG” OR “Arachidonoyl glycerol” OR “HU-210” OR “WIN-55” OR “JWH-015” OR Methanandamide OR “JWH-133”AND Melanoma OR “skin cancer” OR “malignant melanoma” OR melanocarcinoma OR melano-epithelioma OR melanosarcoma AND in vivo OR ex vivo OR animal OR experimental OR xenograft. The reference lists of relevant studies were also checked. Two reviewers (A.B. and N.J.) reviewed the abstracts and full texts independently for inclusions and exclusions. Any differences in inclusion or exclusion were determined by consensus or consultation with a third reviewer (N.M.). The studies and the relevant data were classified and extracted in accordance with the assessed procedure. The titles and abstracts of retrieved articles were then screened in order to select relevant articles for inclusion. Full-text screenings were performed, and relevant data were extracted from these eligible studies. The detailed process of the search as a PRISMA flow chart is presented in Figure 1 .

Flow diagram showing the search process and results used in this study.

2.4. Data Extraction and Synthesis

In total, 622 titles and abstracts (using the inclusion and exclusion criteria) were screened according to the eligibility criteria for inclusion in this study. There were 503 non-duplicated articles detected during this screening of articles obtained via literature search. After screening, a total of 19 studies were selected and were further evaluated to determine which of them were in vivo or in vitro studies, with the latter being excluded. The inclusion/exclusion criteria and main characteristics of the six included studies are presented in Table 1 . This table describes the key findings of this systematic review including the results of melanoma and cannabinoids interactions, studies on tumor growth in mice, description of the specific cannabinoid or receptor involved in the regulation of cell (tumor) proliferation in test subjects, and the corresponding supporting studies.

Table 1

Summary of eligible studies comparing the effects of cannabinoids on melanoma.

First
Author
(Year)
Study Population
(Animals)
Tumor
Induction
(Cell Line)
Study Intervention Dose of Cannabinoid Duration Anticancer Outcomes
Strain Age Number Intervention Control
Hamtiaux
2012
C57BL/6mice 5–weeks n = 6 B16 melanoma cells PEA+URB597
(s.c)
Vehicle 10 mg/Kg 6 days Co-administration of PEA and URB597 resulted in a significant reduction of tumor growth & size
Glodde 2015 C57BL/6mice Wild-type and CB1/CB2-deficient mice 8–10 weeks n = 10 B16 melanoma cells
HCmel12
THC (s.c) Vehicle 5 mg/Kg per day 25 days Inhibits HCmel12 melanoma growth but does not affect B16 and CB1/CB2 deficient HCmel12
Armstrong et al. 2015 Athymic nude mice 5 weeks 20 mice
(n = 5 per group)
Xenograft
CHL-1 cells
THC (oral)
THC-BDS + CBD-BDS (oral)
Temozolomide
Vehicle 15 mg/Kg (daily)
7.5 mg/Kg + 7.5 mg/Kg (daily)
5 mg/Kg (daily)
20 days Reduction in tumor size
THC-BDS + CBD-BDS
≥ THC > TEMO
Blazquez 2006 C57BL/6mice
Nude mice
n = 8 (per group)
n = 6 for each experimental group
B16 melanoma cells WIN55-212-2(s.c)
or
JWH-133 (s.c)
WIN55-212-2 (s.c)
Vehicle 50 mg/day
50 mg/day
50 mg/per3days
8 days
21 days
WIN55-212-2
= JWH-133 in preventing tumor growth
Decreased tumor growth and
metastasis
Kenessey 2012 SCID mice n = 8 HT168-M1 ACEA (i.p) Solvent control 0.24 mg/Kg
1/2 mg/Kg
21 days CB1 agonistic AECA into SCID mice inhibit liver colonization of human melanoma cells
Simmerman 2018 C57BL/6mice 8–12 weeks of age) 18 (n = 6 per group) Murine melanoma cell line, B16F10 CBD (i.p)
Cisplatin (i.p)
Vehicle 5 mg/Kg twice per week
5mg/Kg once per week
Increased the quality of life and movement; significantly decreased growth curve and increased survival curve

Abbreviations: s.c (subcutaneously), i.p (intraperitoneally), BDS (botanic drug substance), CBD (cannabidiol), TEMO (temozolomide: Chemotherapy drug), WIN212-2 and JWH-133 (synthetic cannabinoids), URB597 (inhibitor of the enzyme fatty acid amide hydrolase), PEA (N-Palmitoylethanolamide), THC (Δ⁹-tetrahydrocannabinol), ACEA (synthetic cannabinoid), cisplatin (chemotherapy medication).

2.5. Quality Assessment

The risk of bias was assessed using SYRCLE’s (SYstematic Review Centre for Laboratory animal Experimentation) risk of bias tool for animal studies [39]. According to SYRCLE’s tool selection biases include random group allocation, baseline group allocation, allocation conceal; performance bias contains random hosing, blinding of examiner; detection bias comprises random outcome selection, blinding of assessor; attrition bias and other biases include any randomization, any blinding, size calculation, or temperature control. Two researchers independently screened the literature, extracted the data, and performed the cross-check. In the case of a disagreement, the resolution was reached through discussions with a third researcher.

2.6. Assessment of the Risk of Bias in the Included Studies

In this assessment “YES” indicated low risk and “NO” indicated high risk. The results obtained from a detailed analysis of the six selected studies showed that half of the included studies were classified as a low-risk random group. Half of these studies showed a high risk of the baseline group characteristic. All of these studies had a high risk of allocation conceal, and two of these included studies are at low risk of random housing. All of the studies were at high risk for blinding of an examiner, random outcome selection, blinding of assessor, and attrition bias. For other biases, half of the studies had any randomization and none of them was mentioned for any blinding, size calculation, or temperature ( Table 2 ).

Table 2

Risk of bias assessment in animal studies using SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation) tool *.

Study Selection Bias Performance Bias Detection Bias Attrition Bias Other Bias
Random Group Allocation Baseline Group Characteristics Allocation Conceal Random Hosing Blinding of Examiner Random Outcome Selection Blinding
of
Assessor
Any Randomization Any Blinding Size Calculation Temp Control
Armstrong
2015
L H H H H H H H Y N N N
Blazquez
2006
L L H H H H H H Y N N N
Hamtiaux
2012
L L H H H H H H Y N N N
Glodde
2015
H L H H H H H H N N N N
Kenessey
2012
H H H L H H H H N N N N
Simmerman
2018
H H H L H H H H N N N N

* H = High Risk, L = Low Risk, Y = Clear, N = Not Clear.

3. Results

The result of our search strategy was 622 articles initially identified through database searches. One hundred and nineteen duplicate studies were discarded, leaving 503 single studies. An additional 484 studies were removed after the title and abstract screening, excluding non-English articles, studies not addressing the research question, and expert opinion articles. Nineteen full-text articles were reviewed for eligibility for inclusion in the final analysis. Further evaluation showed that 40%, or six of these 19 records, were in vivo studies and were therefore included in this review. As the focus of this review was on in vivo studies, the in vitro studies were subsequently excluded ( Figure 1 ).

Cannabinoids and Melanoma Cancer

A few studies have evaluated the presence of cannabinoid receptors (CB1 and CB2) and the role of cannabinoids in carcinogenesis and cell proliferation of melanoma in vivo. As a result, Glodde et al. (2015) demonstrated that ∆9-THC significantly reduced the growth of HCmel12 melanomas in mice by about 50%, according to vehicle-treated mice after 25 days. However, this reduction was not observed in mice without the CB1/CB2 receptors, indicating the importance of a CB receptor for the inhibition of metastasis and the possibility of this occurring via a CB receptor-dependent mechanism. This study also provided some new insights into the potential role of natural or synthetic CB receptor agonists in the treatment of cancer types characterized by a pro-tumorigenic inflammatory microenvironment. Armstrong et al. (2015) showed that cannabinoids (THC) induced autophagy in SK-MEL-28, A357, and CHL-1 melanoma cells, through an apoptotic-like mechanism. Co-treatment with cannabidiol (CBD) and ∆9-THC was also observed to exert a synergistic cytotoxic effect on these cells. Using a mixture of THC and the non-psychoactive cannabinoid CBD, a laboratory mimic of the clinical cannabinoid Sativex ® (an oromucosal spray) containing equal amounts of THC and CBD reduced glioma growth in vivo at the same level as an identical dose of THC [40]. The cannabinoid THC was found to exert its antitumor effect on melanoma cells via the activation of non-canonical autophagy and subsequent apoptosis in this study. Hamtiaux et al. (2012) investigated the possibility of enhancing endocannabinoid cytotoxicity using inhibitors of their hydrolysis in the melanoma model. The results of their investigations showed that the co-administration of PEA and URB597 caused a significant reduction in the growth of tumors and their sizes.

In another investigation, ∆9-THC activity resulted in the inhibition of the activation of pro-survival proteins, Akt and pRb, in melanoma compared to the non-tumorigenic melanocytes [41]. The activation of CB receptors with WIN-55,212-2 (synthetic cannabinoids) in vivo caused notable reductions in cell viability, growth of tumor, and metastasis. Another study showed that the systematic administration of ACEA, a stable CB1 agonist, to SCID mice inhibited liver colonization of human melanoma [42]. Simmerman et al. (2018) reported that the administration of cannabidiol repressed the tumor size significantly compared with the untreated group, while cisplatin demonstrated a greater reduction in tumor size but was associated with a lower quality of life ( Table 1 ). Further research is needed to clarify the exact role and particular mechanisms exploring the endocannabinoid and receptors involved behind such a phenomenon.

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4. Discussion

Marijuana is classified as an illicit drug and its use is prohibited in most countries. However, cannabis/hemp strains contain over 120 phytocannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), which are thought to be of therapeutic more importance [22,31,43]. Apart from phytocannabinoids, other classes of cannabinoids such as endocannabinoids and chemically synthetic cannabinoids are known [44]. Cannabinoids have an extensive role in palliative care, which includes inhibition of nausea and emesis related to chemo- or radiotherapy, appetite stimulation, pain relief, mood elevation, and relief from insomnia for some oncology patients [45].

This systematic review was focused on the role of cannabinoids as antiproliferative agents in melanoma in studies carried out in vivo in recent literature. Several studies have shown that cannabinoids can reduce cell proliferation and induce apoptosis in melanoma cells [41,46]. While there is an abundance of literature related to the biological mechanisms for melanoma cancer and their interactions with cannabinoids in vitro, very limited studies have been carried out on the effects of cannabinoids on melanoma cancers in vivo and or evaluated with clinical trials. This is why only six papers were related to the desired in vivo parameters out of the over 622 papers that were screened. Despite the availability of limited information, scientific understandings of the therapeutic role of cannabinoids as antiproliferative and tumor-regression agents remain a significant research interest. The comparatively limited number of in vivo studies probably explains why there were fewer clinical trials on cannabinoid treatment of melanoma reported in peer-reviewed articles. This is because a successful in vivo test is a pre-requisite for clinical trials.

A review of literature has shown that multiple clinical trials have been carried out using CBD and THC to treat a variety of medical issues ranging from post-traumatic stress disorder (PTSD), chronic pain, to multiple sclerosis [47]. In some of the trials evaluated, the use of cannabinoids was found, in addition to alleviating the symptoms of the diseases being targeted, to also improve the quality of sleep in clinical subjects by reducing sleep disturbance episodes and reducing the onset of sleep latency [47]. Preliminary data from some of the clinical trials have indicated that the use of CBD can alleviate the symptoms of acute schizophrenia [48], and the use of THC and/or CBD is thought to potentially reduce chronic pain in some patients and may require further trials for confirmation [49]. For example, THC/CBD extracts have been shown to provide pain relief in some patients with advanced cancer whose pains had not been successfully relieved by opioid pain killers [50]. However, a different review of clinical evidence on the relief of cancer-related pain showed conflicting results, and the authors suggest that there may be limited or no significant evidence of cannabinoids causing a demonstrable reduction in cancer pain [51]. Other clinical trials such as the CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) trial on the use of cannabinoids for the treatment of progressive inflammatory brain disease have shown no beneficial effect of cannabinoid use on disease progression [52].

With respect to cancer, there are limited but hopeful clinical trials relating to the role of cannabinoids for the treatment of malignancies. A study in Israel is studying the efficacy of the use of cannabinoids as a treatment in patients with tumors that are resistant to chemotherapy ( > NCT02255292) [53]. Another study is a phase 1/2 trial that is assessing the combined effect of Sativex ® and temozolomide in patients with recurrent glioblastoma multiforme ( > NCT01812603 and > NCT01812616) [54,55]. Other small clinical trials have shown some regression in tumor sizes associated with the use of cannabinoids or cannabinoid extracts [55].

Out of the six papers on in vivo studies selected in this review, four of them demonstrated the beneficial effects of cannabinoids against melanoma. It is important to note in most of these studies, in vitro assays were initially carried out to validate that the selected treatments had reduced tumor-genesis and proliferation in melanoma cell lines. Firstly, evidence from some of the selected in vivo studies showed that cannabinoids can be used individually to successfully reduce tumor sizes and induce cell death. Two of the selected studies clearly demonstrated this; the use of THC in mice with induced BRAF/NRAS wild-type tumors promoted autophagy in melanoma cells [32]. Similarly, the use of CBD on mice with an induced B16F110 tumor significantly reduced tumorigenicity and tumor size [31].

Secondly, in some instances, the use of cannabinoids can potentially improve the quality of life of cancer patients. When compared to an equally effective non-cannabinoid compound cisplatin, CBD-treated mice had improved movement in and out of the cage and less hostile interactions compared to cisplatin [31]. This behavioral improvement could translate to a potentially better quality of life (less agitation and stress) in some human subjects with melanoma.

Thirdly, using a combination of cannabinoids can also be effective in melanoma treatment. The THC/CBD combination (Sativex ® ) substantially promoted autophagy, apoptosis, and loss of viability in melanoma cells compared to a non-cannabinoid compound, temozolomide [32]. Sometimes, a better treatment effect as a result of synergy was observed, with THC/CBD causing a substantial loss of melanoma viability compared to THC alone [32].

Fourthly, these reductions in tumor size, enhancement of autophagy, and apoptosis can occur in the presence or absence of CB1 and CB2 cannabinoid receptors. Activation of these receptors by cannabinoids and other agonists reduced cell proliferation and metastasis, and promoted the death of cancer cells in in vivo studies [41]. However, in the absence of these receptors, a similar result was observed. In wild-type (WT) and CB1/CB2 receptor-deficient mice, substantial inhibition of tumor growth (skin cancer cells) in both types of mice was observed when THC was used for melanoma treatment [56]. This indicated that cannabinoids can reduce melanoma growth by other mechanisms that do not involve the use of endocannabinoid receptors.

The epidermal layers of the skin are made up of different types of cells such as keratinocytes and melanocytes which are the source of malignant and non-malignant skin cancer [55]. In addition to these cells, the ECS of the skin has also been implicated in skin cancer development, regulation, and control with CB1 and CB2 receptors thought to play important roles based on their interactions with cannabinoids and endocannabinoids [55]. Reviews of past work by Velasco et al. (2015) have shown that cannabinoid anti-tumor activities occur via the induction of cancer cell death, inhibition of the spread of cancer cells, and the promotion of immune activities that suppress tumor [57].

A number of studies support the notion that cannabinoids could potentially enhance the immune response, thereby preventing growth and spread of tumors. An in vivo melanoma xenograft model showed that the activity of WIN 55,212-2 promotes tumor regression efficiently in the immunocompetent mice against immunodeficiency [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]. Another study showed that CBD, THC, and R(+)-methanandamide make lung cancer cell susceptible to lysis by lymphokine killer cells [59]. The underlying mechanism is thought to include upregulation of ICAM-1 (intercellular adhesion molecule 1) on the surface of cancer cells by cannabinoids leading to crosslink with the related lymphocyte function antigen-1 on the surface of killer cells. Moreover, another study indicated that infiltration reduction for macrophages and neutrophils in animals treated with THC of experimental skin lead to tumor regression [56,58]. Therefore, cannabinoids may facilitate an antitumor immune response through independent mechanisms by triggering a more responsive immune system to combat cancer or provide favorable conditions such as localized reduction in pro-carcinogenic inflammatory microenvironment within the cancer tissue. However, a previous study showed that THC accelerated the differentiation of breast cancer cells as a consequence of inhibiting the anti-tumor immune response [60]. Hence, further research is required to elucidate the role of cannabinoids in tumor progression and immune interactions within the cancer tissue. More recently, there are a substantial surge in the use of immunotherapy and cannabinoids. A recent study showed that combination of cannabis and nivolumab as an immunotherapy agent for patients with advanced malignancies decreased the response rate, and did not affect the progression-free survival or overall survival, and without relation to cannabis composition [61].

CB1 and CB2 cannabinoid receptor-stimulation by cannabinoid agonists can lead to the apoptosis of cancer cells. This occurs because the stimulation of the receptors leads to the synthesis and release of a compound called ceramide. Ceramide synthesis stimulates the production of endoplasmic reticulum stress-related factors although cannabinoids such as THC upregulate stress-regulated proteins such as p8 or NUPR1. These stress-proteins can regulate (inhibit) tumor generation and production alongside other transcriptional factors such as endoplasmic reticulum-ATF4, TRIB3, and CHOP, and enhance autophagy [57]. Cancer regulation can also occur independently of CB1 and CB2 receptors [62].

In conclusion, evidence from these in vivo studies suggest that the use of THC and CBD not only inhibited tumor growth and reduced tumor size but also seemed to improve the quality of life in animal models [31]. A synergistic approach (using two cannabinoids in combination) may be more beneficial for melanoma treatment than the use of individual cannabinoids [32] with a potentially improved quality of life in some patients. Therefore, future in vivo studies should include both individual cannabinoid and combined cannabinoid-based approaches for the treatment of melanoma and the investigation of the mechanism underpinning the synergistic effects observed. In addition, given the large number of in vitro studies, future reviews will be needed to identify the potential underlying mechanisms of cannabinoids involved in the inhibition of melanoma and to contribute further to our understanding of the complex endocannabinoid system involvement in the treatment of cancer.

Author Contributions

Conceptualization and design, N.M. and A.B.; methodology, A.B. and N.J.; data curation, A.B. and N.J.; formal analysis, A.B., and N.J.; writing—original draft preparation, A.B., N.J., and S.A.S.; writing—review and editing, N.M., T.J.P., and S.A.S.; supervision, N.M. and T.J.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research is funded by MGC Pharmaceuticals Limited, Australia. Ava Bachari is a Ph.D. student supported by an RMIT University Scholarship.

CBD’s Impact on Melanoma Cells

Hannah Yohe ’21 has read the news articles and seen the new businesses popping up touting the benefits of medical marijuana and cannabidiol, or CBD. She’s watched as friends and family purchase CBD products that offer promises of helping with joint inflammation or anxiety. While the York College Biology major is a believer in the health benefits of medical marijuana, she knew there was a lot of research ahead.

“I wanted to find the gaps in what still needed to be studied,” she says. “I’m really interested in this topic and thought I had an opportunity to dive into research while it’s still early in the process.”

Yohe found that melanoma, a form of skin cancer that can easily spread to other organs, was an area that had a lot of research gaps. York College had melanoma cells available in the lab, so Yohe just had to work to get access to CBD for her independent research project.

“You can’t just go out and buy CBD, despite what you see on the shelves of health stores or even at the gas station,” she says. “There are often other additives in it, and you need a pure form to be able to conduct research. Sigma-Aldrich biotechnology provided lab quality CBD for Yohe’s research. Finally, she could get to work.

A lot of people still have uncertainty about the health benefits of medical marijuana because they don’t understand it, Yohe says. While there are more than 100 chemicals in cannabis, the two most common are THC (short for tetrahydrocannabinol) and CBD. Both can be found in marijuana and hemp, although marijuana has more THC, which produces the high, and hemp has more CBD, which has other medicinal properties without the high.

The FDA has approved one CBD-based drug. Epidiolex is a treatment for several severe forms of rare childhood epilepsy. The National Institutes of Health clinical trials database shows more than 160 trials involving CBD that are either active or recruiting.

“It’s a subject that has a lot of opportunity for understanding,” Yohe says. “Getting into the research now is a great foundation for the work I could be doing in my career.”

While many people think of medical marijuana as a treatment for symptoms, such as anxiety or inflammation, Yohe found that CBD was actually instrumental in treating the root of melanoma. Other medical research shows CBD reduces the size of brain tumors, decreases growth in colon cancer and pancreatic cancer, and slows down blood vessel formation.

Yohe’s research backed up her theory that CBD could reduce the melanoma, but some of her experiments were cut short because of COVID-19. Despite not getting to all of her proposed experiments, she was able to use lab equipment specific to her research and learn some fascinating things about CBD.

“A lot of things we learn in the classroom can be theoretical, so you don’t see them in real life,” she says. “It’s cool when you can do the experiment yourself and get actual data and see that this stuff is real. We can test our theories and learn by doing.”

Cannabinoids and their derivatives in struggle against melanoma

Melanoma is one of the most aggressive malignances in human. Recently developed therapies improved overall survival rate, however, the treatment of melanoma still remains a challenging issue. This review attempts to summarize recent advances in studies on cannabinoids used in the setting of melanoma treatment. Searches were carried out in PubMed, Google Scholar, Scopus, Research Gate. Conclusions after analysis of available data suggest that cannabinoids limit number of metastasis, and reduce growth of melanoma. The findings indicate that cannabinoids induce apoptosis, necrosis, autophagy, cell cycle arrest and exert significant interactions with tumor microenvironment. Cannabinoids should be rather considered as a part of multi-targeted anti-tumor therapy instead of being standalone agent. Moreover, cannabinoids are likely to improve quality of life in patients with cancer, due to different supportive effects, like analgesia and/or anti-emetic effects. In this review, it was pointed out that cannabinoids may be potentially useful in the melanoma therapy. Nevertheless, due to limited amount of data, great variety of cannabinoids available and lack of clinical trials, further studies are required to determine an exact role of cannabinoids in the treatment of melanoma.

Graphic abstract

Introduction

The endocannabinoid system is dysregulated in numerous pathological conditions, including malignancies. These alterations might include function and/or expression of cannabinoid receptors and enzymes, or affect concentration of various cannabinoid receptor ligands [1]. Recently, cannabinoids have received increasing amount of interest in the setting of treatment of various cancers. However, majority of data comes from in vitro and animal studies, therefore, most of potential uses of cannabinoids still require validation in patients.

The use of cannabinoids is a widely debated crucial issue. Currently, the medical cannabis is legalized for medical use in 19 European Union countries, Canada and 36 states in US [2, 3]. In EU, law permits use of cannabis based drugs for various conditions and symptoms such as cancer treatment, chronic pain, nausea, anorexia, muscle spasticity, AIDS, multiple sclerosis, and seizures [2]. Cannabis, however, contains not only cannabinoids, but also terpenes and flavonoids. These different compounds of cannabis were also reported to exert the anti-tumorigenic actions [1]. The best studied groups of substances isolated from cannabis are cannabinoids. Their therapeutic potential has been observed in several malignancies, including breast, prostate, lung, skin, pancreatic and bone cancers, as well as lymphoma and glioma [4]. In last few years, efforts have been made to determine the role of cannabinoids in the setting of melanoma treatment.

Melanoma: epidemiology, prognosis, risk factors

Melanoma represents 1.6–5.5% of all cancers [5, 6]. Unlike most of the neoplasms, it often affects young people. It accounts for majority of deaths caused by skin cancers in total. Globally, in 2018, there were approximately 324,635 new cases of melanoma and 57,043 deaths caused by it in 185 countries [5, 6]. In the last few years, there was significant mortality decline in melanoma, due to new therapies for metastatic disease [6]. Nevertheless, melanoma is one of the most aggressive malignancies. It harbors one of the highest mutation frequencies among human cancers [7]. The leading driver of mutagenesis in melanoma is ultraviolet light. Tremendous mutation burden correlates with response to different therapies [8]. Once metastases occur, the prognosis is considered to be poor. On the genetic level, crucial determinant of anti-tumor immune response to melanoma is tumor heterogeneity. Two major origins of aggressiveness of melanoma are: degree of genetic diversity of the tumor and number of distinct clones composing it. These factors impede treatment of metastatic melanoma and are linked to response to the immune therapy and patients’ survival [9].

The main risk factor for developing melanoma is excessive exposure to ultraviolet radiation. The highest risk occurs in individuals with a phenotype of blond or red-hair, light-colored eyes, freckles and pale skin. Moreover, presence of multiple dysplastic or benign melanocytic neavi, immunosuppression, positive family history and skin sunburn, especially during childhood and adolescence also contribute to the development of melanoma [10, 11].

Treatment options of melanoma

The most important way to reduce mortality in melanoma is its early detection. Therapy of localized melanoma is well established and primarily based on wide local surgical excision with proper margins [12]. The 5-year survival rate at this stage reaches 99% [13]. Management of metastatic melanoma has been dramatically reshaped over last decade. From usage of conventional chemotherapy like dacarbazine, it evolved into immunotherapy and molecularly targeted therapies [14]. Main and most effective agents are immune checkpoint inhibitors, including anti-programmed death-1 (anti-PD1) and anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) antibodies. Implementation of these agents resulted in increase of 5-year survival rate from 15 to 20% up to 52%, but at cost of high toxicity [15, 16]. Moreover, in patients with the BRAF V600E mutation, the antibodies are likely to have high response rates from use of molecularly targeted, the therapies serine-threonine kinases inhibitors (inhibitors of BRAF, MEK, KIT) [17]. However, the response to these agents is generally less durable and a 5-year survival rate reached maximum 28% in patients with metastatic melanoma treated with the most favorable BRAF and MEK inhibitors combination [18]. This therapy, however, seems important for younger patients (aged < 40 years), who are more likely to have BRAF V600 mutation, which allows predicting sensitivity to inhibitors of BRAF and MEK, as do KIT exon 11 mutations to KIT inhibitors [8]. Overall, the combined therapy with BRAF and MEK inhibitors is superior within the first 6 months, becoming after that point inferior to PD-1 blockers alone or in combination with CTLA-4 blockers [19]. Efficiency of current therapies is often limited due to their toxicity, undesirable side effects, frequent metastases and quickly growing resistance mechanisms [20, 21]. Studies on new molecular targets and immunotherapeutic options are still ongoing (Table 1). Along that appeared novel ideas, like an application of oncolytic virus talimogene laherparepvec (T-VEC) [22].

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Cannabinoids: mechanisms of action and pathways

Cannabinoids exert their actions mainly by binding to G-protein-coupled CB1 and CB2 receptors and other receptors, such as peroxisome proliferator activated receptors PPARs), transient receptor potential (TRP) channels and other G-protein-coupled orphan receptors, like GPR18, GPR55 or GPR119 and serotonin 1A receptor (5-HT1A) [23,24,25]. Moreover, a role of lipid raft cannot be excluded [26, 27]. Hundreds of phyto- and synthetic cannabinoids demonstrate diverse pharmacological effects on the particular cell types by acting as agonists or antagonists/inverse agonists of CB1 and CB2 receptors, however, only a few have found their place in clinical use [28].

The cannabinoid CB1 receptors are expressed in neurons of the central nervous system, peripheral nerve terminals and non-neuronal tissues, such as adipose tissue, lungs, liver, spleen, uterus and testis among others [29, 30]. In general, the activation of CB1 receptors is responsible for psychiatric effects, such as alterations in movement, sensory learning, analgesia, anxiety, appetitive behaviors and abuse of cannabinoids. Additionally, CB1 agonists reveal a variety of effects—anti-depressant, anti-nociceptive, anti-convulsant, anti-depressant, anxiolytic, anti-emetic, orexigenic, anti-proliferative and anti-migration. The CB1-selective antagonists/inverse agonists have anti-diabetes effect and may be helpful in reducing body mass and treating drug dependency [28].

The cannabinoid CB2 receptors are mainly expressed in the immune system cells [31]. The activation of CB2 receptors is responsible for cannabinoids’ anti-inflammatory, immunomodulatory, anti-cancer, anti-spasmatic, anti-nociceptive, neuroprotective, osteoprotective and anti-obesity effects [28, 32, 33]. Against common belief, the CB2 receptors are expressed in the central nervous system, however, their role is not yet fully understood. Their expression in the central nervous system and other tissues seems to be upregulated in some of pathological conditions [34, 35]. The CB2-selective agonists have been paid a lot of attention lately, because of their therapeutic potential in treating pain, inflammation, neuroinflammatory or neurodegenerative diseases and cancer, while avoiding the psychotropic effects related to the CB1 receptor activation [28, 36]. Most of them are investigated in preclinical studies with success, but only few of them reached the stage of clinical trials [28, 37].

Both, CB1 and CB2 receptors are members of the G protein-coupled receptors (GPCRs) and primarily couple to pertussis toxin-sensitive G proteins of the Gi and Go classes [38]. They suppress adenylyl cyclase, thereby formation of cyclic AMP, induce activation of mitogen-activated protein kinase (MAPK) pathways [38, 39]. Moreover, stimulation of CB1 receptor activates extracellular signal-regulated kinase 1 or 2 (ERK1/2), p38 MAPKs and c-Jun N-terminal kinases (JNKs) [30, 39]. Besides MAPKS, CB1 receptor also activates the PI3K/Akt pathway [30, 40, 41]. Due to limited number of studies on CB2 receptor activation of MAPK and other pathways, data in that area is limited. The CB1 receptor was reported to activate other G proteins in particular cell types in the ligand-dependent manner [39, 42]. Another difference between CB1 and CB2 receptors is that that the former receptors act through modulation of activity of ion channels. They activate G-protein-coupled inwardly rectifying potassium channel (GIRKs), inhibit N-type calcium channels and have various effect on L-type calcium channels [42,43,44].

The precise description of cannabinoid receptor signaling is complex and exceeds the scope of this article. The more detailed information on signal transduction pathways have been described elsewhere [39, 42, 43, 45].

Phytocannabinoids and synthetic analogs

Cannabinoids are the major compounds of the Cannabis sativa L. plant, which psychotropic and therapeutic properties have been used by mankind since thousands of years. Cannabis plant contains more than 120 different active constituents, named phytocannabinoids. The pharmacological effect of whole plant extract intake is the sum of compounds’ effects and is inconstant due to the varying proportions of phytocannabinoids in different environment. Phytocannabinoids used in research on melanoma are: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) [46].

The biologically active synthetic analogues of cannabinoids used in research on melanoma belong to the group of Δ 9 -THC-like analogs or aminoalkylindole compounds. JWH-133 (as a synthetic derivative of THC) is a potent analog with high affinity to CB2 receptors. WIN55212-2 (as aminoalkylindole derivative) is agonist of both CB1 and CB2 receptors [38].

Anandamide (AEA) is an endogenous cannabinoid, partial agonist of CB1 and CB2 receptors. Its synthetic analogues, more selective towards CB1 receptor, are: arachidonyl-2′-chloroethylamide (ACEA) and arachidonylcyclopropylamide (ACPA). The other endogenous cannabinoid, fatty acid amine, is palmitoylethanolamide (PEA) [38].

AM251, one of the arylpyrazoles, is an inverse agonist of CB1 receptors, usually used to block CB1 receptor-mediated effects [38]. The effects of these compounds regarding to melanoma are reviewed below.

Cannabinoids-related adverse effects

The CB1 receptor due its high expression in central nervous system is the main receptor responsible for psychotropic effects caused by cannabinoids. Because CB1 receptors are widespread in mammalian tissues, therefore, their activation leads to numerous adverse effects through the body and limits its therapeutic application. Crucial side effects of CB1 receptor ligands include neurological disorders, cardiovascular dysfunction, digestion failure and potential for addiction [28, 30]. On the other hand, CB1 receptor antagonists/inverse agonists cause gastrointestinal disorders and psychiatric disturbances, such as depression, anxiety, and suicidal ideation [28, 47].

The CB2 receptor agonists were reported to be well tolerated [48, 49]. Possible side effect of CB2 receptors activation, due to their predominance in immune cells is immune dysfunction and immunosuppression [50]. Lately possible adverse effects of CB2 receptor agonists on reproductive system have been reported, i.e. decreased sperm count, impairment of placental development and reduced offspring growth [51]. Nonetheless, adverse effects caused by the particular substances are more complex, due to their various effects on different receptors and off targets actions. For instance, the application of cannabidiol (CBD) causes diarrhea, decreased appetite and somnolence, pyrexia and vomiting [52]. WIN55,212-2 application may lead to anxiety, recognition memory impairment and brain network functional connectivity impairment [53, 54].

In last years the issue of determining cannabinoids’ therapeutic potential in different neoplasms emerged, which seems important to be evaluated. The aim of this review is to point out the mechanisms of action of cannabinoids and determine if cannabinoids have a potential to be included into the treatment of melanoma.

Materials and methods

The literature review was undertaken by searching following terms in combination (“Cannabinoids” OR “Cannabis sativa” OR “CBD” OR “Cannabidiol” OR “THC” OR “Tetrahydrocannabinol” OR “AEA” OR “anandamide” OR “ACEA” OR “arachidonylcyclopropylamide” OR “PEA” OR “palmitoylethanolamide” OR “AM251” OR “JWH-133” OR “URB597” OR “WIN 55,212-2” OR “2-AG” OR “arachidonoyl glycerol”) AND (“melanoma” OR “melanocarcinoma” OR “melanosarcoma” OR “melano-epithelioma” OR “A375”or “SK-MEL” OR “FM55” OR “B16” OR “HCmel12”) on electronic databases, PubMed, Scopus, and additionally Research Gate and Google Scholar. The results were limited to December 2020. Relevant studies’ reference lists were also hand-searched. The inclusion criteria were research studies on the action of cannabinoids on melanoma only, both in vivo and in vitro. The exclusion criteria were: reviews, commentaries and non-English articles. All the abstracts and full texts were reviewed independently by two authors (P.M. and M.D.) focusing on criteria of inclusion and exclusion. Totally, 414 records were detected using electronic databases. After screening, 376 articles were excluded as irrelevant and 38 articles were assessed for eligibility. The relevant studies were selected by second full-text screening. After removing duplicates and assessment, only nine experimental studies were included in this review.

The main limitations in this review are those related with selection of previously published original studies (methods of search outlined above and appropriateness of these research papers with the inclusion/exclusion criteria).

Results

Numerous mechanisms of action of endocannabinoid system have been described in different carcinomas [55]. The debate on the role of elevated levels of endocannabinoids and increased cannabinoid CB receptors’ expression in neoplasms is still ongoing [56]. Nevertheless, the knowledge of how do cannabinoids work in melanoma is still limited, yet it is progressing. Multiple studies report that melanoma expresses CB1 and CB2 receptors, and other receptors like GPR family or TRPV1 [27].

Role of the CB1 receptors The CB1 receptors in melanoma cells were localized in the membrane, cytoplasm and cytoskeleton. Genes of this receptor (CB1) were proved to be similar in different, unrelated melanoma cell lines [57]. They pay considerable contribution to the anti-tumor effects of cannabinoids. Activation of CB1 receptors causes significant induction of apoptosis, arrests cells in the G2/M phase of the cell cycle and, in higher concentrations of CB1 receptor agonists, might even lead to cell necrosis. They also contribute to the anti-migratory effect of cannabinoids. Moreover, the combinations of various CB1 agonists and inverse agonists lead to additive anti-proliferative effects [57]. However, in one study, it was suggested that the CB1 receptors may contribute to the development of melanoma, particularly in A375 and 501Mel cell lines, by promoting cell growth, migration, clonogenicity, cell cycle progression and activation of ERK and Akt signaling pathways [58]. It is supported by the observation that silencing of the CB1 receptor or delivering CB1 antagonist like SR141716 induces cell cycle arrest in the G1/S-phase in other tumors, while it does not lead to apoptosis or necrosis [59, 60]. Gathered data suggest that CB1 agonists and antagonists may work by off-target mechanisms, making the interpretation complex and ambiguous [26, 58].

Role of CB2 receptors The CB2 receptors are overexpressed in the melanoma cells, but not expressed in normal surrounding tissues [61]. It is suggested that CB2 receptors might be associated with melanoma development and activators of CB2 receptors may be used in the treatment of this skin cancer [61]. In contrast, one study presented that absence of the CB1 and CB2 receptors did not affect development of chemically induced skin tumors [62]. Besides, the activation of CB2 receptors can also improve blood–brain barrier function via endothelial cells, which may reduce number of melanoma brain metastases. This effect is achieved by reduction of adhesion and trans-endothelial migration of melanoma cells. The best effect of over 40% reduction was observed when both, brain endothelial cells and melanoma cells were pre-treated with the CB2 agonist—versus 25–30% reduction without pretreatment [63].

Cannabinoid derivatives in the treatment of melanoma

Δ9-Tetrahydrocannabinol (THC)

THC mimics endocannabinoids and binds to both CB1 and CB2 receptors, as partial agonist. Therefore, it presents the mixed agonist–antagonist effect which is likely to be dependent on the expression of CB receptors, presence of agonists or endocannabinoids and the cell types [46]. THC causes loss of cell viability in a dose-dependent manner by activation of apoptosis and autophagy in melanoma cells both, in vitro and in vivo (Table 1). THC causes death of malignant melanoma cells in concentrations, which are safe for normal melanocytes [64, 65]. Viability of most of non-transformed cells seems to be not as sensitive on cannabinoids as cancerous cells, however, highly proliferative cells may undergo apoptosis and cell death [64, 66]. In another study, the THC treatment in the mouse model significantly reduced HCmel12 cell line growth but, THC did not affect B16 cell line and mice lacking the CB1 and CB2 receptors till the end point of the study [62]. Moreover, there was no therapeutic effect in in vitro models, which stands in contrast to other conducted studies [64, 65]. Lack of the action might have occurred due to very low expression levels of CB1/CB2 receptors in this model, suggesting the important role of CB1/CB2 receptors in inhibiting melanoma.

WIN 55,212-2

Activation of CB receptors by the mixed CB1 and CB2 agonist—WIN 55,212-2 can significantly block the formation of new blood vessels, decrease proliferation, tumor growth and induce apoptosis of melanoma cells in the mouse exografted tumor model (Table 1). The main proposed mechanism of action in this model was rapid inhibition of the pro-survival Akt pathway via tumor suppressor retinoblastoma protein, resulting in cell cycle arrest at G1-S transition. These effects, together with reduced metastasis are independent on immune status of animals and are similar to THC, selective for melanoma cells versus normal melanocytes [64]. Another potential mechanism of the anticancer action of WIN 55,212-2 involves membranes lipids. In one of the studies, WIN 55,212-2 caused melanoma cell death independent on CB1, CB2 and VR-1 receptors, via lipid raft machinery [26]. The possible role of lipid rafts was also stated during anandamide (AEA) tests [27].

Cannabidiol

CBD has very low affinity to both CB1 and CB2 receptors and acts as antagonist/inverse agonist of the CB1, a partial agonist of the CB2 and negative allosteric modulator of the CB1 receptors, and at sub-micromolar concentrations, as an antagonist of both CB1 and CB2 receptors [46]. Multiple receptors affected by CBD and various mechanisms take part in modulation of oncogenic signaling and redox homeostasis [67] (Table 1). Recent study presents beneficial therapeutic effect of CBD in a murine model. The administration of CBD in mice with injected subcutaneously melanoma caused significant extension of survival time and decrease in tumor growth compared to the control animals without treatment [68]. The combination of THC with CBD causes stronger inhibition of cell viability in both in vitro and in vivo studies [65].

Anandamide (AEA), its analogues and inhibitors

AEA is the CB1/CB2 receptor agonist, TRPV1 agonist, putative GPR55 agonist, induced in the A375 melanoma cell line a concentration-dependent cytotoxicity and decrease in cells viability (Table 1). Potential factors involved in action of AEA were by-products of its metabolism derived by cyclooxygenase-2 (COX-2) and lipooxygenase (LOX), and possibly contribution of lipid raft modulation, GPR55 and CB1 receptors. Effect of AEA was mitigated by AM251 (a CB1 receptor antagonist/inverse agonist), which did not affect cell viability by itself. Due to the lack of CB2 receptors in used cell line and no effect of a selective CB2 receptor agonist (JWH133) on cell viability, the effect of AEA was attributed mainly to AEA by-products and CB1 receptors [27]. It is worth to note that in this particular cell line the lack of CB2 receptors may be ascribed to clonal difference, because in other A375 melanoma cell lines, the CB2 receptor was expressed [64], or even overexpressed [61].

In another study, AEA and its more selective towards CB1 receptor analogues, the arachidonyl-2′-chloroethylamide (ACEA) and 2-methyl-2′-F-anandamide (Met-F-AEA) exerted the anti-proliferative effect on Ht168-M1 and WM983B melanoma cells. This action was assigned to induction of apoptosis, G2/M arrest and cell necrosis [57]. In contrast to previous study, AM251 (an inverse agonist at the CB1 receptor) was observed to have even stronger pro-apoptotic effect and to cause G2/M phase cell cycle arrest [57, 69]. On the other hand, one of these studies confirmed that AM251 potentiates the effect of CB1 agonists [57]. It was found that B16 melanoma cells produce enzymes that degrade endocannabinoids and the blockade of hydrolysis by various inhibitors, including URB597 (a relatively selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH)), which leads to increase of endocannabinoids levels and even greater increase of cytotoxicity of AEA and palmitoylethanolamide (PEA). The most potent combination was PEA and URB597, when using together causes higher apoptosis and necrosis rates in vitro than each of the tested agents alone. It was confirmed in in vivo model of B16 melanoma in C57BL/6 mice, where PEA-URB597 combination reduced growth of the tumor and reduced its size [70].

JWH-133

The selective CB2 agonist JWH-133 was reported in one study to exert no effect on melanoma in vitro [26], but in another, it inhibited tumor growth and decreased cell proliferation in vivo [64] (Table 1).

The above-mentioned studies suggest a significant role of endocannabinoid system in development and pathophysiology of human melanoma and imply the role of cannabinoids in the treatment of this cancer. Particular substances exert different actions on endocannabinoid system, resulting in various effects on melanoma. Some of them present off-target mechanisms or involve less studied receptors. They can be divided into natural substances, with broader spectrum of action and synthetic ligands with often more accurate action.

Discussion

The knowledge about the role of cannabinoids in health and disease is still progressing. Due to encouraging results of application of the cannabinoids in various cancers and their relatively low toxicity, they began to gain interest in the field of melanoma treatment.

There are couple of factors that impact the signaling of cannabinoids. They are exerting their actions through various signaling pathways, not only by widely described CB receptors. These actions may be mediated via adenosine mechanisms, strychnine-sensitive glycine receptors, GPR55, GPR119 and 5-HT (serotonin) receptors or TRP channels [23, 46]. Moreover, cannabinoids are likely to interact with various signaling pathways [42]. The full action of cannabinoids may be a result of simultaneous activation of various receptors present on the same cell [71]. Cannabinoids also exert different effects on various tissues and even cell lines and some effects vary between in vitro and in vivo models [57, 62, 64, 65, 70]. For example: cells of A375 melanoma line express high levels of COX-2, which may affect the actions of particular cannabinoids like AEA or AM251 [27, 69], and AEA produces effects in in vitro model, but not in vivo of HT168-M1 cell line [57]. Various levels of expression of receptors and pathways in particular tissues are likely not to be the only explanation of this phenomenon. The role of tumor microenvironment cannot be excluded [62, 64]. In contrast, in HCmel12 cell line, THC produced effects in in vivo models, but not in in vitro. Potential explanation was a low expression level of CB1 and CB2 receptors in this cell line, interaction with immune cells and tumor microenvironment [62]. Some cannabinoids can inhibit tumor growth in vivo by antagonizing the infiltration of immune cells in characteristic pro-inflammatory microenvironment. THC modulates the activity and number of macrophages, natural killer cells and decreases function of T-cells [62]. These all taken together suggest that molecular mechanisms of cannabinoids’ anti-tumor actions are complex and not fully understood.

In the case of melanoma, most important actions of cannabinoids described so far are decrease of cells viability by increase of apoptosis, necrosis [70] and cell cycle arrest [57, 69].

Potential anti-proliferative mechanisms involved in melanoma cell apoptosis caused by cannabinoids are caspase-dependent apoptotic pathway [26, 27, 62, 65], inhibition of AKT and dephosphorylation of retinoblastoma protein [64], ERK phosphorylation [26], lipid raft machinery [26, 27] and activation of autophagy [65] (Fig. 1).

Summary of destructive mechanisms of actions exerted by cannabinoids on melanoma

Moreover, cannabinoids slow down disease progress by reduction of metastasis and tumor vascularization [4, 63, 64, 66]. Potential mechanisms involve inhibiting epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR) in tumors, induction of changes in endothelial cells and down-regulation of molecules involved in adhesion like: intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and metalloproteinases (MMPs) [4, 63, 72].

The role of autophagy induced by cannabinoids remains not completely clear. It can either cause cell death, by autonomous death pathway, or activation of apoptosis. However, it can also act as a cytoprotective factor or source of energy to resist cell death caused by cytotoxic therapy. It seems to vary with cannabinoids and the cell types [65, 73]. In melanoma, cannabinoids seem induce non-canonical autophagy that leads to cell death via apoptosis. This mechanism involves TRIB3 and leads to inhibition of Akt/mTORC1 signaling [65]. These diverse mechanisms of action of cannabinoids may serve as a potential therapy in case of triple negative melanomas (harboring wild-type BRAF, NRAS and PTEN), which do not respond to a novel immunotherapy.

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Due to large variety of cannabinoids, there are many potential derivatives, which may be found useful in the therapy of melanoma. Recently, some new cannabinoid derivatives and CB receptors ligands have emerged, that may have therapeutic potential in various cancers [28]. Some of them are reported to be devoid of any major side effects. For instance, a recently described orally active cannabinoid peptide (Pep19—the ligand of CB1), lacks of effects on central nervous system or heart rate alterations [74]. There is a high need of further both, in vitro and in vivo studies to determine their interactions with widely used drugs.

Other potentially useful compounds involved in endocannabinoid system function may be inhibitors of enzymes degrading cannabinoids. For example, the enzymatic hydrolysis of endocannabinoids like AEA and PEA is done mainly by the fatty acid amide hydrolase (FAAH) and the N-acylethanolamine-hydrolyzing acid amidase (NAAA) [75, 76]. Positive effects of inhibiting these enzymes may be observed also in case of melanoma treatment [70]. Moreover, FAAH inhibitors have been described to spare adverse psychotropic effects [77, 78].

Cannabinoids may complement currently used melanoma pharmacotherapies and counteract several side effect of chemiotherapeutics. Besides potential anti-tumor actions of cannabinoids, the compounds also produce different effects, which can potentially improve quality of life in patients with cancers. Most of this data, however, is limited and often requires studies and trials of higher quality. For instance, the cannabinoids are potentially efficient drugs in decreasing cancer pain and, therefore, increasing the patients’ quality of life [79, 80]. Cannabinoids have been also implied in treatment of cachexia, where they increased the patients’ appetite [81]. Application of cannabinoids may be beneficial in some patients with sleep disorders [82]. Some cannabinoids have been found useful in treatment of vomiting associated with chemotherapy, especially in patients, who did not respond to traditional anti-emetic drugs [83]. It is important to keep in mind that some people, often adolescents and young adults, may use cannabinoids from their own initiative as recreational drugs [84].

Despite potential mitigating action of cannabinoids on side effects of other melanoma pharmacotherapies, data about complementing these compounds together remain limited. So far one study assessed a problem of such interactions and involved nivolumab, the programmed death-1 (PD-1) inhibitor, one of main anti-melanoma agents. The usage of cannabis containing different concentrations of THC and CBD during immunotherapeutic treatment with nivolumab decreases response rate, without affecting progression-free survival and overall survival. There was no significant relation to cannabis composition, dose or the way of use [85]. However, the main limitation was a retrospective model of the study with relatively small group of patients and a non-representative sample of patients with melanoma. Results have suggested that combining these drugs should be carried out with caution and further studies are required to assess the way of combining cannabinoids with currently used anti-melanoma immunotherapy.

The main limitation of this comparative overview is small number of the available studies, different types of used melanoma cell lines, various incubation times and techniques used. In in vivo studies, each murine model of melanoma has its advantages and disadvantages, which may impact the results [86]. For example, xenograft models lack immune system, therefore, they do not provide the proper microenvironment for the tumor [87]. All these factors seem to be important due to great variety of genetic diversity of melanoma.

Conclusion

Cannabinoids seem to be promising agents in the setting of melanoma treatment. However, due to limited number of studies and data available their role in modulation of this tumor progression remains unclear. They are likely to be part of multi-targeted drugs combination therapy, rather than the single drug treatment. More advanced molecular studies are necessary to evaluate the exact role of cannabinoids in melanoma treatment. Only few of the conducted studies determined interactions of cannabinoids with currently used melanoma therapies, therefore, it would be beneficial to investigate this problem. It requires further investigation through both, in vitro and in vivo studies, to determine the exact role of cannabinoids in melanoma treatment. Undoubtedly, the treatment of melanoma requires multi-targeted drugs combination strategy, potentially including cannabinoids.

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Acknowledgements

This study was supported by a grant from Medical University of Lublin, Lublin, Poland (DS 474/2020).

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Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090, Lublin, Poland

Paweł Marzęda, Małgorzata Drozd, Paula Wróblewska-Łuczka & Jarogniew J. Łuszczki

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Marzęda, P., Drozd, M., Wróblewska-Łuczka, P. et al. Cannabinoids and their derivatives in struggle against melanoma. Pharmacol. Rep 73, 1485–1496 (2021). https://doi.org/10.1007/s43440-021-00308-1

Received : 29 March 2021

Revised : 30 June 2021

Accepted : 05 July 2021

Published : 15 July 2021

Issue Date : December 2021

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