Nonmelanoma skin cancer (NMSC) stands as the most prevalent form of cancer among Americans. Given that ultraviolet (UV) radiation exposure is a major risk factor for the development of skin cancer, dietary antioxidants (AOs) emerge as potential allies in preventing free radical-mediated DNA damage and tumorigenesis secondary to UV radiation. This article delves into the role of dietary AOs in preventing tumorigenesis, outlining targeted dietary AOs and reviewing research results on oral AOs supplements compared to dietary AOs intake via whole foods.
Understanding Nonmelanoma Skin Cancer
NMSC, encompassing basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), surpasses the combined incidence of breast, lung, prostate, and colon cancers. While public health campaigns have aimed to modify behaviors that increase UV exposure, significant exposure persists through intentional tanning, use of tanning beds, and incidental exposure.
The Role of Antioxidants in Preventing Tumorigenesis
NMSC tumorigenesis is an extended, multistage process, consisting of initiation, promotion, and progression. Damage from free radicals plays a crucial role in the initiation of this process. UV radiation and exposure to environmental pollution generate free radicals, molecules that contain unpaired electrons and induce direct oxidative damage to proteins, lipids, and DNA. Most free radicals in the body exist in the form of reactive oxygen species (ROS), which are known to damage the bases and deoxyribosyl backbone of DNA. Free radicals (mainly as singlet oxygen or hydroxyl radicals) damage DNA through the formation of oxidized pyrimidine bases and single-strand DNA breaks.
Free radicals damage not only DNA but also cellular proteins and lipids. Direct oxidation of enzymatic proteins leads to the activation of pathways that produce new proteins. These processes can increase cell proliferation and inflammation. Free radical-mediated peroxidation of lipids promotes the destruction of the cell phospholipid bilayer. Furthermore, UV radiation can lead to immunosuppression, hampering the ability of immune cells to recognize and combat cancer cells.
Antioxidants combat these processes through a number of mechanisms that prevent these oxidative reactions and subsequent DNA and cellular damage. Some have also been shown to act through the upregulation of genes encoding for enzymes, which are capable of neutralizing ROS. While the body has mechanisms in place to neutralize ROS, accumulative oxidative stress from UV exposure can inundate these mechanisms. Therefore, researchers have turned to exogenous AOs. Preliminary studies in humans have shown that individuals with BCC have higher serum markers of oxidative stress and lower serum levels of dietary AOs.
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Multiple animal studies have found that AOs provide protection against skin cancer. Some have focused on supplementation with single AOs, while others have focused on varying combinations. In hairless mice exposed to UV light, a significant reduction in the incidence of malignant and precancerous lesions was seen in mice that had received supplemental vitamin C in the diet. In another study of mice exposed to a topical carcinogen, supplementation with beta-carotene reduced the number of tumors by 32%, while vitamin E supplementation reduced the number of tumors by 25%. In another study of hairless mice exposed to UV radiation, 30% of the mice fed a regular diet developed frank SCC, while only 7% of those fed a special diet developed SCCs. This diet included a mixture of vitamins C and E with glutathione and butylated hydroxytoluene. In a later study of mice treated with a potent carcinogen, a nutrient mixture added to their diet significantly inhibited the incidence and multiplicity of skin tumors.
Laboratory studies and further animal studies have identified potential mechanisms of action for these effects. It is important to note that the beneficial effects noted in these studies may be dependent on other factors. In fact, researchers write that “under certain conditions both water-soluble antioxidants (e.g., vitamin C and urate) and the lipid-soluble antioxidant tocopherol (vitamin E), promote or even induce peroxidation.” For example, in vitro studies have found that in mild oxidative states and in the absence of other co-AOs such as vitamin C, vitamin E may act as a prooxidant. While there is clear benefit in multiple laboratory and animal studies, studies performed in human subjects have provided conflicting results.
Targeted Dietary Antioxidants
Vitamin C
Vitamin C, or ascorbic acid, is a water-soluble vitamin present most abundantly in fruits and vegetables. It serves as a cofactor of multiple different enzymes in the human body including prolyl and lysyl hydroxylase. These enzymes are essential for the synthesis, cross-linkage, and stability of collagen. In a study of cultured keratinocytes, researchers found that vitamins C and E counteracted the increase in ROS induced by acute UVB irradiation, and in combination protected against UVB-induced apoptosis. In normal human oral keratinocytes, researchers compared the protective roles of vitamins C and E in oxidative stress imposed by smokeless tobacco. Vitamins C and E, alone and in combination, offered significant protection. Vitamin C also impacts DNA repair. In a study of human dermal fibroblasts treated with vitamin C, researchers found an increased expression of genes associated with DNA replication and repair, and the fibroblasts demonstrated faster repair of oxidatively damaged DNA bases.
Vitamin E
Vitamin E differs from the other AOs reviewed here in that it actually represents a group of closely related molecules. These 8 different molecules include 4 tocotrienols and 4 tocopherols. These fat-soluble substances are found in foods such as soybeans and wheat germ, and the naturally occurring form D-alpha tocopherol has the greatest biological activity. When synthesized, however, it forms together with l-alpha tocopherol, and this l-isomer has less biological activity. Vitamin E is lipid soluble and has been shown to prevent membrane lipid peroxidation by ROS. In a study of mouse keratinocytes, vitamin E treatment prior to UVB radiation was able to reduce the UVB-associated epidermal damage. In human fibroblasts exposed to UVA light, vitamins C and E showed photoprotective potential.
Carotenoids
Carotenoids are a group of plant compounds that impart a bright color to the different fruits and vegetables in which they are found, such as carrots, squash, and sweet potatoes. There are hundreds of carotenoids, with about 40 said to be present in the typical human diet. In laboratory and animal studies, carotenoids have been shown to impact carcinogenesis, with several postulated mechanisms. Another mechanism focuses on the AO capabilities of carotenoids, which have the ability to quench singlet oxygen and scavenge free radicals. In a study of cells from a human liver cell line, carotenoids provided protection against oxidant-induced lipid peroxidation. Of note, this protection was found to be independent of any proretinoid activity. In animal studies, beta-carotene has suppressed lipid peroxidation.
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Selenium
Selenium is a trace mineral and is found in different food sources, including plants grown in soil with high selenium concentrations, as well as some meats, fish, and other sources. Selenoproteins are proteins that contain selenium in the form of an amino acid. In laboratory studies, selenium has demonstrated effects against carcinogenesis. Selenium derivatives have induced apoptosis in different human tumor-derived cell lines, including skin cancer. In a mouse carcinogenesis model, a selenium compound significantly reduced preneoplastic skin lesions, with a significant decrease in cell proliferation and a significant enhancement of apoptosis. In the same carcinogenesis model, treatment with selenium also resulted in the inhibition of lipid peroxidation in the skin, as well as the elevation of AO enzymes, including catalase and superoxide dismutase.
Antioxidant Supplements vs. Whole Foods
There are four AO supplements for which large, longer-term human research studies are available. Studies of these four supplements in humans have not supported their role in skin cancer prevention. Randomized controlled trials (RCT) of beta-carotene, selenium, and combination supplements (including various combinations of vitamin C, vitamin E, beta-carotene, selenium, and other substances) have not been shown to reduce the incidence of NMSC in men or women.
Studies estimating dietary intake of AOs via the combination of supplements and whole foods have not shown promise in reducing the incidence of NMSC. However, these studies have considered the intake of AOs to be simply additive. Research supports the idea that AOs provided in the form of isolated supplements function in a different manner than that provided in the form of whole foods.
At this time, there are limited studies evaluating serum levels of these specific AOs in NMSC prevention. Conflicting results have been seen in these small studies. In addition, the issue of timing when performing serum studies is an important one. While in one study lower than mean selenium levels were associated with skin cancer, it was noted that neoplastic tissue sequesters selenium. In addition, it is not known how well serum AO levels reflect dietary intake. In the case of serum cholesterol, for example, it is well known that genetic differences can result in markedly different serum cholesterol levels despite the same level of dietary intake.
Challenges in Study Design
Designing a study to evaluate the effects of AO intake via whole foods is very challenging. One small, well-designed dietary intervention trial showed promise. While the intervention did result in increased intake of vitamin C, beta-carotene, and fiber, the study was focused on the effects of a low-fat diet. A larger experimental study also looked at the effects of a low-fat diet. The subjects were given a dietary plan which entailed decreasing fat intake to less than 20% of caloric intake and consuming at least 5 servings of fruits and vegetables daily. This study did not demonstrate efficacy, but the study design must be considered in evaluating the results. A separate prospective observational study did not focus on macronutrients (i.e., fat), but rather focused on the “combined consumption of foods,” and it did find that a “vegetable and fruit” pattern decreased NMSC as opposed to a “meat and fat” pattern.
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The Importance of Whole Foods
Given the results of large-scale, randomized, placebo-controlled trials, we conclude that these 4 AO supplements, in the reported doses and for the studied duration of intake, are not effective tools for skin cancer prevention. One reason for this reported difference in efficacy may be due to the biochemistry of AOs and their downstream effects. The process of oxidation, and correspondingly antioxidation, is not a straightforward, single-step process, nor is it a straightforward chain of events. In an interventional study, male smokers treated with beta-carotene supplements over 5-8 years had a higher incidence of lung cancer. A later study of smokers also showed an increase in lung cancer among subjects taking beta-carotene supplements with vitamin A supplements. Animal studies helped to identify a possible explanation. In a study of ferrets exposed to smoke, markedly different effects were seen with low dose of beta-carotene supplementation (corresponding to dietary intake) versus high dose intake (corresponding to pharmacologic doses).
The biochemistry of this process provides an explanation. Free radicals can cause damage due to the presence of an unpaired electron. AOs such as beta-carotene may neutralize free radicals by providing an electron of their own. In the process, though, the AO itself now contains an unpaired electron. Vitamin C can act to neutralize this newly created prooxidant.
Further animal studies have shown that the explanation is likely to be even more complex. In cases of a limited (as opposed to a well-balanced) diet, beta-carotene supplements have resulted in significant exacerbation of UV carcinogenesis. The researchers explained that, when beta-carotene exerts its AO effects, the newly created beta-carotene radical cation contains an unpaired electron and is therefore strongly oxidizing. The researchers concluded that “the photoprotective effect of beta-carotene reported earlier by others…might depend on interaction with other dietary factors that are either absent, or present in ineffectual concentrations, in the semi-defined diet in which exacerbation of UV carcinogenesis occurs.
A related conclusion was drawn by Chang et al. While their meta-analysis of 10 large RCTs with vitamins and supplements known to have AO properties showed no reduction of NMSC incidence, the researchers did draw a distinction between supplements and whole foods. They stated that when consumed in a fruit or vegetable,…
Additional Dietary Considerations
Obesity and Melanoma
Maintaining a healthy weight is one of the most important strategies for cancer prevention, including melanoma. Studies show overweight and obese men carry a 31 percent increased risk of malignant melanoma. Research continues on whether this risk is the same for women, however, women who were overweight or obese reported spending less time exposing skin to the sun. In fact, some studies have shown that women with a higher body mass index (BMI) may have a lower risk for developing malignant melanoma, basal cell carcinoma and squamous cell carcinoma, compared to men with a high BMI. Researchers in the UK have also identified a potential genetic link between obesity, overeating and melanoma risk. They report that a variation in the FTO gene, called intron 8, may be a culprit in this connection and further study should be conducted. Preliminary research in mice also shows caloric restriction may help slow melanoma cancer progression.
The Gut Microbiome
The microbiome also plays an important role on stress and mental health, and vice versa. “It’s called the gut-brain axis,” says Cohen. “It’s this reciprocal loop that’s going on. The health of the microbiome influences stress and stress influences the microbiome.”
Additional Antioxidants
Studies have found that higher intake of retinol-rich foods, such as fish, milk, eggs, dark green leafy vegetables, and orange/yellow fruits and vegetables led to a 20 percent reduced risk of developing melanoma. Studies show selenium-rich diets may also reduce risk for melanoma and support survivorship. Foods rich in this antioxidant include Brazil nuts, scallops, lobster, barley, oats, whole wheat, wheat germ and milk. Preliminary studies with green tea also show possible benefits in melanoma prevention, but research remains in its infancy.
Foods to Include in Your Diet
- Tomatoes: Rich in lycopene, a powerful antioxidant that protects the skin from UV-induced damage.
- Carrots and Sweet Potatoes: Excellent sources of beta-carotene, which your body converts into vitamin A.
- Green Tea: Loaded with polyphenols, particularly epigallocatechin gallate (EGCG), which help fight inflammation and inhibit the development of cancer cells.
- Berries: Packed with antioxidants like vitamin C and flavonoids.
- Nuts and Seeds: Rich in vitamin E and healthy fats.
- Fatty fish: Fatty fish such as salmon, sardines, mackerel, herring and albacore tuna are chock full of omega-3s.
- Dark Green Leafy Vegetables and Orange/Yellow Fruits and Vegetables: Higher intake of retinol-rich foods, such as fish, milk, eggs, dark green leafy vegetables, and orange/yellow fruits and vegetables led to a 20 percent reduced risk of developing melanoma.
- Selenium Rich foods: Foods rich in selenium include Brazil nuts, scallops, lobster, barley, oats, whole wheat, wheat germ and milk.
Foods to Limit or Avoid
- Processed Meats: High in nitrates and preservatives, which have been linked to an increased risk of several cancers, including skin cancer.
- Fried Foods: Contain unhealthy trans fats and advanced glycation end products (AGEs) that contribute to oxidative stress and inflammation.
- Charred or Grilled Meats: Produce chemicals known as heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs).
- Alcohol: Heavy alcohol consumption can weaken the immune system and dehydrate the skin, making it more vulnerable to sun damage and cellular mutations.
- Highly Processed Foods: Often contain artificial additives, unhealthy fats, and high sodium levels, all of which can promote inflammation and oxidative stress.
- Red Meat: Aim for no more than 18 ounces of cooked red meat per week.
- Sugar-sweetened beverages and energy-dense foods: Added sugars and other high-calorie sweeteners (such as high-fructose corn syrup) are often used in sugar-sweetened beverages and energy-dense foods (for example, traditional “fast food” or ultra-processed foods (or UPFs).
Dietary Supplements
While dietary supplements can provide some benefit, they also have risks. Dietary supplements are not regulated the same way as medicines are. Eating a diet rich in vegetables, fruits, and other plant foods may lower cancer risk, but there’s little consistent evidence that dietary supplements do the same. Some high-dose supplements containing nutrients such as beta-carotene and vitamins A and E may actually increase the risk of some cancers. Vegetables and fruits contain many different compounds that probably work together to have healthful effects. Some supplements claim to provide the same nutrition as vegetables and fruits, but they usually contain only a small fraction of what whole foods provide. Food is the best source of vitamins, minerals, and other important food components.
The Mediterranean Diet
One great power regimen combining a wealth of anticancer nutrients is the famed Mediterranean diet, a plant-based diet rich in active, potent antioxidants and anti-inflammatories. A mélange of the traditional diets of people living around the Mediterranean, it features nutritionally rich foods such as cruciferous and green leafy vegetables, tomatoes, citrus fruit, fresh herbs, fish high in omega-3 fatty acids, wine and olive oil.
Lifestyle Choices
Skin cancer is one of the most common forms of cancer worldwide, but the good news is that many risk factors can be managed through simple lifestyle choices.
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