Vitamin D and Skin Cancer: A Controversial Society. Literature Update and Review. / Vitamina D y cáncer cutáneo: una asociación controvertida. Actualización y revisión de la literatura.

Vitamin D (VD) deficiency has been associated with various tumors. However, the association between VD and skin cancer is controversial. Although in non-melanoma skin cancer, adequate or even high levels of VD can be associated with a higher risk of developing tumors, this could be biased by the direct association between sun exposure and VD levels. Regarding melanoma, results are contradictory. Most studies analyzed state that higher levels of VD could reduce the risk of melanoma, be associated with melanomas with better prognosis and with an enhanced antitumor response, and also with fewer adverse events associated with melanoma immunotherapy. However, prospective studies of adequate methodological quality are still needed to assess the association between VD levels and its supplementation and development/prognosis in skin cancer.

Nutrient-Based Approaches for Melanoma: Prevention and Therapeutic Insights.

Melanoma, a prevalent and lethal form of skin cancer, remains a formidable challenge in terms of prevention and treatment. While significant progress has been made in understanding its pathogenesis and treatment, the quest for effective prevention strategies and therapeutic approaches remains ongoing. Considering the increased advancements in understanding the dynamic interplay between nutrients and melanoma, we aim to offer a refreshed perspective on nutrient-based approaches for melanoma prevention and adjunctive therapy. In contrast to other studies, we have innovatively provided a detailed exposition of the nutrients' influences on melanoma prognosis and treatment. This review firstly examines various nutrients, including antioxidants (namely vitamins A, D, C, and E; selenium; and caffeine), polyunsaturated fatty acids, and flavonoids, for their effects and underlying mechanisms in reducing melanoma risk. Among these nutrients, caffeine shows the most promising potential, as it is supported by multiple cohort studies for its protective effect against melanoma. In contrast, there is a certain degree of inconsistency in the research of other nutrients, possibly due to inherent differences between animal studies and epidemiological research, as well as variations in the definition of nutrient intake. To comprehensively investigate the impact of nutrients on melanoma progression and therapeutic approaches, the following sections will explore how nutrients influence immune responses and other physiological processes. While there is robust support from cell and animal studies regarding the immunomodulatory attributes of vitamins D and zinc, the anti-angiogenic potential of polyphenols, and the cell growth-inhibitory effects of flavonoids, the limited availability of human-based research substantially constrains their practical relevance in clinical contexts. As for utilizing nutrients in adjuvant melanoma treatments, multiple approaches have garnered clinical research support, including the utilization of vitamin D to decrease the postoperative recurrence rates among melanoma patients and the adoption of a high-fiber diet to enhance the effectiveness of immunotherapy. In general, the effects of most nutrients on reducing the risk of melanoma are not entirely clear. However, several nutrients, including vitamin D and dietary fiber, have demonstrated their potential to improve the melanoma prognosis and enhance the treatment outcomes, making them particularly deserving of clinical attention. A personalized and interdisciplinary approach, involving dermatologists, oncologists, nutritionists, and researchers, holds the promise of optimizing melanoma treatment strategies.

The Role of Dietary Antioxidants in Melanoma and Nonmelanoma Skin Cancer.

Dietary supplements, including vitamins and their derivatives, have been utilized within the field of dermatology to treat a variety of skin conditions. Antioxidants inhibit oxidation and decrease cellular damage caused by free radicals, potentially preventing DNA damage due to UV radiation. Laboratory studies have demonstrated promising results supporting the possible role of antioxidants for prevention of skin cancer related to UV exposure. We review the effects of frequently encountered antioxidants and vitamins suggested for the chemoprevention of melanoma and nonmelanoma skin cancer (NMSC) in humans.

Nutritional Interventions for Patients with Melanoma: From Prevention to Therapy-An Update.

Melanoma is an aggressive skin cancer, whose incidence rates have increased over the past few decades. Risk factors for melanoma are both intrinsic (genetic and familiar predisposition) and extrinsic (environment, including sun exposure, and lifestyle). The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma, and research is focusing on strategies to optimize them. Obesity is an established risk factor for several cancer types, but its possible role in the etiology of melanoma is controversial. Body mass index, body surface area, and height have been related to the risk for cutaneous melanoma, although an 'obesity paradox' has been described too. Increasing evidence suggests the role of nutritional factors in the prevention and management of melanoma. Several studies have demonstrated the impact of dietary attitudes, specific foods, and nutrients both on the risk for melanoma and on the progression of the disease, via the effects on the oncological treatments. The aim of this narrative review was to summarize the main literature results regarding the preventive and therapeutic role of nutritional schemes, specific foods, and nutrients on melanoma incidence and progression.

Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.

PURPOSE: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes. METHODS: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline. RESULTS: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress. CONCLUSION: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.

MMP-9 and IL-1ß as Targets for Diatoxanthin and Related Microalgal Pigments: Potential Chemopreventive and Photoprotective Agents.

Photochemoprevention can be a valuable approach to counteract the damaging effects of environmental stressors (e.g., UV radiations) on the skin. Pigments are bioactive molecules, greatly attractive for biotechnological purposes, and with promising applications for human health. In this context, marine microalgae are a valuable alternative and eco-sustainable source of pigments that still need to be taken advantage of. In this study, a comparative in vitro photochemopreventive effects of twenty marine pigments on carcinogenic melanoma model cell B16F0 from UV-induced injury was setup. Pigment modulation of the intracellular reactive oxygen species (ROS) concentration and extracellular release of nitric oxide (NO) was investigated. At the cell signaling level, interleukin 1-ß (IL-1ß) and matrix metallopeptidase 9 protein (MMP-9) protein expression was examined. These processes are known to be involved in the signaling pathway, from UV stress to cancer induction. Diatoxanthin resulted the best performing pigment in lowering MMP-9 levels and was able to strongly lower IL-1ß. This study highlights the pronounced bioactivity of the exclusively aquatic carotenoid diatoxanthin, among the others. It is suggested increasing research efforts on this molecule, emphasizing that a deeper integration of plant ecophysiological studies into a biotechnological context could improve the exploration and exploitation of bioactive natural products.

Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial.

Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13-24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9-38.4) against placebo (median 19.05 ng/mL; IQ range 13.0-25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44-16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.

Phenolic Compounds in Prevention and Treatment of Skin Cancers: A Review.

Several clinical studies have shown that exposure of skin to solar ultraviolet (UV) radiation causes adverse effects, such as inflammation, oxidative stress and DNA damage. As a result, different skin disorders can arise, among which are skin cancer, including non-melanoma skin cancer (NMSC) and melanoma (MM). Phenolic compounds are plant-derived secondary metabolites with a well-known antioxidant activity, able to counteract the negative effects of UV radiation. In this review, we discuss the effects of some selected phenols on NMSC and MM, demonstrating that they can be useful in the prevention and in the treatment of these types of tumors. Moreover, we report the mechanisms by which these phenols carry out their antitumor action. In vitro and in vivo studies have highlighted that many phenols are capable of inducing photoprotection, apoptosis and autophagy. They can also reduce DNA methylation, tumorigenesis, tumor incidence and proliferation. Moreover, we describe some examples of plant extracts, whose anticancer activity appears to be better than that of single phenols. A great concordance of results emerged, despite the differences in experimental methods. Therefore, the knowledge compiled here could provide the basis for conducting some well-organized clinical trials to validate the chemopreventive and the therapeutic potential of some phenolic compounds in patients with NMSC and MM.

Activation of the tumor suppressive Hippo pathway by triptonide as a new strategy to potently inhibit aggressive melanoma cell metastasis.

Metastatic melanoma has a very high mortality rate despite the availability of chemotherapy, radiotherapy, and immunotherapy; therefore, more effective therapeutics are needed. The Hippo pathway plays an inhibitory role in melanoma progression, but the tumor suppressors Salvador homolog-1 (SAV1) and large tumor suppressor 1 (LATS1) in this pathway are down-regulated in melanoma. As a result, the downstream oncogenic Yes-associated protein (YAP) is active, resulting in uncontrolled melanoma growth and metastasis. Therapeutics for remedying SAV1 and LATS1 deficiency in melanoma have not yet been reported in the literature. Here, we show that the small molecule triptonide (MW 358 Da) robustly suppressed melanoma cell tumorigenicity, migration, and invasion. Furthermore, triptonide markedly reduced tumor growth and melanoma lung metastasis in tumor-bearing mice with low toxicity. Molecular mechanistic studies revealed that triptonide promoted SAV1 and LATS1 expression, strongly activated the tumor-suppressive Hippo pathway, degraded oncogenic YAP via the lysosomal pathway, and reduced levels of tumorigenic microphthalmia-associated transcription factor (MITF) in melanoma cells. Triptonide also strongly inhibited activation of AKT, a SAV1-binding signaling protein. Collectively, our results conceptually demonstrate that induction of SAV1 and LATS1 expression and activation of the tumor-suppressive Hippo pathway by triptonide potently inhibits aggressive melanoma cell growth and metastasis. These findings suggest a new strategy for developing therapeutics to treat metastatic melanoma and highlight a novel drug candidate against aggressive melanoma.

Sun Protective Clothing and Sun Avoidance: The Most Critical Components of Photoprotection in Patients With Melanoma.

BACKGROUND: Ultraviolet radiation is the main modifiable risk factor for melanoma which can be reduced by avoiding excess sun exposure. OBJECTIVE: We sought to explore (1) sun protective practices, (2) effectiveness of these sun protective practices, and (3) vitamin D supplementation in patients with melanoma. METHODS: Using the National Health Interview Survey, the authors conducted a cross-sectional analysis to investigate sun protective behaviors and sunburns among adults with melanoma compared with those without skin cancer. We calculated adjusted odds ratio (aOR), 95% confidence interval (95% CI), and p-values using logistic regression. RESULTS: Patients with melanoma reported increased use of sun avoidance, shade, sunscreen, long sleeves, and hats, but had similar sunburn rates compared with those without skin cancer. Only sun avoidance and long sleeves were associated with decreased odds of sunburn. Patients with melanoma also reported decreased vitamin D supplementation. CONCLUSION: Although it is reassuring that patients with melanoma practice sun protective behaviors, this does not always translate into reduced sunburns. Physicians should emphasize the importance of photoprotection, especially sun avoidance and sun protective clothing, to reduce future melanoma risk.

Sunscreens in the United States: Current Status and Future Outlook.

Incidence rates of nonmelanoma skin cancer and melanoma have been on the rise in the USA for the past 25 years. UV radiation (UVR) exposure remains the most preventable environmental risk factor for these cancers. Aside from sun avoidance, sunscreens continue to provide the best alternative protection. UVR directly damages DNA and causes indirect cellular damage through the creation of reactive oxygen species, the sum of which leads to cutaneous immunosuppression and a tumorigenic milieu. The current generation of sunscreens protect from UVR through two main mechanisms: absorption and deflection. In the USA, the Food and Drug Association (FDA) regulates sunscreen products which are considered over-the-counter drugs. With the release of new FDA testing and labeling requirements in 2011 and the enactment of the Sunscreen Innovation Act in 2014, sunscreen manufacturers are now required to evaluate their products not only on the sun protection factor (SPF) but also on broad-spectrum UVA protection. The American Academy of Dermatology Association and the American Academy of Pediatrics have provided specific recommendations for proper sun protection and sunscreen usage with the continual goal of increasing public awareness and compliance with appropriate sun protective measures. Antioxidants, photolyases, and plant polyphenols remain an interesting avenue of research as additives to sunscreens or stand-alone topical or oral products that appear to modulate the immunosuppressive effects of UVR on the skin. Additionally, although UVR induces endogenous cutaneous production of vitamin D, its damaging effects overshadow this positive benefit, especially in light of the ease of achieving recommended amounts of vitamin D through diet and supplementation.

Are anti-inflammatory foods associated with a protective effect for cutaneous melanoma?

The aim of this systematic narrative review is to answer the following research question: are anti-inflammatory foods or food components associated with a protective effect for melanoma development? Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, a systematic review was conducted. All cohort studies (n = 18) so far on diet and cutaneous melanoma were reviewed. Out of the 18 cohort studies, seven investigated the role of coffee on melanoma and six studies found a protective effect. Food components considered as anti-inflammatory, such as vitamin D, vitamin A, folic acid, niacin, vitamin C, omega-3 fatty acids, and carotenoids (ß-carotene, lutein, zeaxanthin, and lycopene), were not associated with a protective effect for melanoma. Other anti-inflammatory food items, such as tea, fruits, and vegetables, except for citrus fruits that were borderline associated with an increased risk, were not associated with cutaneous melanoma. In conclusion, the only anti-inflammatory food item that was consistently associated with a protective effect for cutaneous was coffee in particular caffeinated coffee.

Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth.

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming.

A Hybrid Eukaryotic-Prokaryotic Nanoplatform with Photothermal Modality for Enhanced Antitumor Vaccination.

Cytomembrane-derived nanoplatforms are an effective biomimetic strategy in cancer therapy. To improve their functionality and expandability for enhanced vaccination, a eukaryotic-prokaryotic vesicle (EPV) nanoplatform is designed and constructed by fusing melanoma cytomembrane vesicles (CMVs) and attenuated Salmonella outer membrane vesicles (OMVs). Inheriting the virtues of the parent components, the EPV integrates melanoma antigens with natural adjuvants for robust immunotherapy and can be readily functionalized with complementary therapeutics. In vivo prophylactic testing reveals that the EPV nanoformulation can be utilized as a prevention vaccine to stimulate the immune system and trigger the antitumor immune response, combating tumorigenesis. In the melanoma model, the poly(lactic-co-glycolic acid)-indocyanine green (ICG) moiety (PI)-implanted EPV (PI@EPV) in conjunction with localized photothermal therapy with durable immune inhibition shows synergetic antitumor effects as a therapeutic vaccine. The eukaryotic-prokaryotic fusion strategy provides new perspectives for the design of tumor-immunogenic, self-adjuvanting, and expandable vaccine platforms.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma.

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.

Targeting Mutated Plus Germline Epitopes Confers Pre-clinical Efficacy of an Instantly Formulated Cancer Nano-Vaccine.

Personalized cancer vaccines hold promises for future cancer therapy. Targeting neoantigens is perceived as more beneficial compared to germline, non-mutated antigens. However, it is a practical challenge to identify and vaccinate patients with neoantigens. Here we asked whether two neoantigens are sufficient, and whether the addition of germline antigens would enhance the therapeutic efficacy. We developed and used a personalized cancer nano-vaccine platform based on virus-like particles loaded with toll-like receptor ligands. We generated three sets of multi-target vaccines (MTV) to immunize against the aggressive B16F10 murine melanoma: one set based on germline epitopes (GL-MTV) identified by immunopeptidomics, another set based on mutated epitopes (Mutated-MTV) predicted by whole exome sequencing and a last set combines both germline and mutated epitopes (Mix-MTV). Our results demonstrate that both germline and mutated epitopes induced protection but the best therapeutic effect was achieved with the combination of both. Our platform is based on Cu-free click chemistry used for peptide-VLP coupling, thus enabling bedside production of a personalized cancer vaccine, ready for clinical translation.

Essential oils: from prevention to treatment of skin cancer.

The increasing incidence of cutaneous malignancies signifies the need for multiple treatment options. Several available reviews have emphasized the potential role of various botanical extracts and naturally occurring compounds as anti-skin-cancer agents. Few studies relate to the role of chemoprevention and therapeutic activity of essential oils (EOs) and EO components. The present review summarizes an overview of chemopreventive, anti-melanoma and anti-nonmelanoma activities of EOs from various plants and EO components in in vitro and in vivo models with special emphasis on skin cancer. Also, the mechanisms by which EOs and EO components exert their effects to induce cell death are presented.

Next-Gen Therapeutics for Skin Cancer: Nutraceuticals.

Growing modernization and lifestyle changes with limited physical activity have impacted diet and health, leading to an increased cancer mortality rate worldwide. As a result, there is a greater need than before to develop safe and novel anticancer drugs. Current treatment options such as chemotherapy, radiotherapy and surgery, induce unintended side effects, compromising patient's quality of life, and physical well-being. Therefore, there has been an increased global interest in the use of dietary supplements and traditional herbal medicines for treatment of cancer. Recently, nutraceuticals or "natural" substances isolated from food have attracted considerable attention in the cancer field. Emerging research suggests that nutraceuticals may indeed prevent and protect against cancer. The intent of this article is to review some of the current spice-derived nutraceuticals in the treatment of melanoma and skin cancer.

Bioaccessible selenium sourced from Se-rich mustard cake facilitates protection from TBHP induced cytotoxicity in melanoma cells.

Selenium (Se) is an essential dietary supplement that resolves inflammatory responses and offers antioxidant cytoprotection. In this study, we present the data on the cytoprotective effect of Se-rich mustard protein isolated from mustard cultivated in seleniferous soils in Punjab, India. The concentrations of total Se in mustard seed, oil-free mustard cake, and mustard protein were 110.0 ± 3.04, 143.0 ± 5.18, and 582.3 ± 6.23 µg g-1, respectively. The cytoprotective effect of Se-rich mustard protein was studied on tert-butyl hydroperoxide (TBHP)-induced cytotoxicity in a mouse melanoma cell line (B16-F10). When compared with TBHP treated cells (where no viable cells were found), Se-rich protein made bioaccessible through simulated gastrointestinal digestion protected melanoma cells from cytotoxicity with decreased levels of oxidative stress resulting in 73% cell viability. Such an effect was associated with a significant increase in glutathione peroxidase activity as a function of bioaccessible Se and its response towards cytoprotection.