The Role of Dietary Antioxidants in Melanoma and Nonmelanoma Skin Cancer

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted.