**5. Chemoprevention with topical and dietary antioxidants, phytochemicals, and vitamin supplementation**

Chemoprevention is the use of natural or synthetic agents to prevent or reverse the develop‐ ment of cancer [21]. Sunscreen use is considered a form of chemoprevention because it contains compounds, such as avobenzone and octyl salicylate, that inhibit UVR from damaging the skin. Supplementation of sunscreens with various phytochemicals and antioxidants has been shown to improve the function of sunscreens in preventing photodamage [13]. Oral intake of certain vitamins, antioxidants, and plant extracts can provide systemic protection as well.

A diet rich in fruits and vegetables has generally been associated with lowering the risk of a variety of diseases and cancers, including skin cancer. Regular consumption of fruits and vegetables was associated with a decreased risk of SCC in a dietary study of 1360 adults in Nambour, Australia. In this study it was also found that a diet high in meat and fat was positively associated with the development of SCC but not BCC [36]. Fruits and vegeta‐ bles contain bioactive phytochemicals, such as flavonoids, polyphenols and carotenoids. These compounds can boost antioxidant and immune system defenses in the body, including in the skin [37]. Carotenoids and flavonoids naturally protect plants from solar UVR, and consumption of these phytochemicals can provide systemic photoprotection for humans [8]. Polyphenols from tea have been shown to protect against UVB-induced contact sensitization, inflammation, carcinogen-induced cancer of the skin, lung, and esophagus in rodent models [37].

Photooxidative damage occurs when the antioxidant defense mechanisms of the skin are overwhelmed by UV-induced ROS, particularly from UVA. ROS that contribute to photocar‐ cinogenesis and photoaging include singlet oxygen, superoxide radical anion, hydroxyl radical, perhydroxyl radical, and hydrogen peroxide [10, 13, 37-39]. Endogenous antioxidants that scavenge for ROS include superoxide dismutase, glutathione peroxidase, ascorbate, alpha-lipoic acid, and catalase [16]. Excessive ROS generated during UV exposure depletes endogenous antioxidants, and causes a state of oxidative stress in cells that can damage cellular proteins, lipids, DNA, trigger apoptosis, and contribute to photocarcinogenesis [14]. Incorpo‐ rating antioxidants into sunscreens can ameliorate UV-induced tissue damage and promote DNA repair [13].

inflammatory and immunosuppressive effects of UVB, topical application of green or white tea has been shown to completely prevent the formation of 8-OH-dG adducts in human skin [21]. The reduction of DNA damage, aberrant cell signaling, inflammation, and immunosup‐ pression are mechanisms exhibited by teas and tea extracts that contribute to their anti-cancer

The amount of pre-treatment time and concentration of green tea polyphenols required to obtain optimal protection on human skin was elucidated in a study by Elmets et.al. In this study, skin on the back of six human subjects was pre-treated for 30 minutes with 0.25-10% solutions of green tea polyphenols. The skin was then irradiated with a solar simulator at twice the individual's minimal erythema dose (MED). At 24, 48, and 72 hours post-exposure erythema was quantified with a chromameter and biopsies were taken from the exposed sites. Erythema was found to be reduced in a dose-dependent manner at all time points and with all doses of green tea polyphenol that were used (figure 1). Pre-treatment with the polyphenols was noted to work best when applied immediately before exposure as opposed to several hours before exposure. Analysis of the biopsies revealed a 66% reduction in the number of sunburn cells, significantly less Langerhans cell migration at 4 days post-exposure, and a 55% reduction

with 5% green tea polyphenols significantly protected against UVA-induced erythema in that experiment [9]. The results of this study indicate that the use of green tea polyphenols is most effective at protecting the skin from UVR when used at a concentration of 0.25% or greater, with the greatest protection observed when applying a 10% solution 30 minutes before irradiation. Adding green tea polyphenols to sunscreens could enhance broad spectrum

**Figure 1.** Effect of green tea polyphenols (GTP) on the erythema response evoked by 2-MED solar simulated radiation. Data represent the mean ± standard error of the mean erythema index at 24, 48, and 72 hours after irradiation with a solar simulator. Measurements were made with a chromameter on 6 volunteers. Areas of skin were pretreated with indicated concentration of an extract of green tea (GTE) 30 minutes before UV exposure. Reprinted from Cutaneous photoprotection from ultraviolet injury by green tea polyphenols, Journal of the American Academy of Dermatology, 44(3):425-32, Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H, (2001) with permission from Elsevier.

In a parallel experiment, Elmets et.al tested separate green tea polyphenols for ability to inhibit erythema on human subjects irradiated with solar simulated UVR. The polyphenols tested

protection since they have been demonstrated to reduce UVA-induced erythema.

UVA only, and pre-treatment

Skin Cancer Prevention Strategies http://dx.doi.org/10.5772/55241 219

in DNA lesions. Subjects were also irradiated with 135 J/cm2

properties.

Human studies with antioxidant supplementation to sunscreens have been successful at demonstrating the benefits of including antioxidants in the formulation. In a human study, the combination of a several antioxidants, including ascorbyl phosphate, tocopherol acetate, *Echinacea pallida* extract, chamomile extract, and caffeine, with sunscreen best protected the skin compared to sunscreen alone after repetitive irradiation with solar simulated UVR [40]. A significant inhibition of UVR-induced melanin synthesis was observed in the presence of antioxidants alone. There was a synergy between the antioxidants and broad spectrum sunscreen, making the combination more protective than either the antioxidants or sunscreen alone. The antioxidant alone was able to prevent hyperproliferation and thickening of the epidermis that is a typical biological response to chronic UVR exposure. UV-induction of cytokeratin 16 and MMP9 was also suppressed by antioxidant cocktail and sunscreen combi‐ nation [40]. In another study using a similar combination of antioxidants, sunscreen with antioxidants or sunscreen alone were equally able to protect against immunosuppression as measured by immunohistochemical staining for Langerhans cells. Less induction of tissue remodeling protein MMP1 was observed with the sunscreen plus antioxidant formulation [13]. Taken together, this data demonstrates additive or synergistic effects of antioxidants for photoprotection.

#### **5.1. Green tea**

Tea (*Camellia sinensis*) drinking has been associated with health in many cultures. Green tea consumption has been associated with reduced cancer risk, including SCC [17]. It has been demonstrated in mouse skin tumor models that green tea inhibits photocarcinogenesis [37]. Epigallocatechin-3-gallate (EGCG) makes up approximately 40% of all the polyphenols found in green tea, and it is believed to be the main polyphenol responsible for the beneficial health effects of green tea [12, 37]. White and black teas also have protective effects. Theaflavins, the polyphenols found in black tea, can inhibit the UVB-induced activation of cell signaling through AP-1, MAPK, and extracellular matrix receptor-activated kinase [17]. Topical application of white or green teas have been shown to protect against the loss of Langerhans cells after solar simulated UVR exposure in both human subjects and in an *ex vivo* skin explant model [21]. In another human study, EGCG inhibited UVB-induced erythema and inflamma‐ tion. Fewer leukocytes infiltrated the skin when EGCG was applied prior to irradiation with UVB, and less prostanoids were synthesized [37]. In addition to being able to suppress the inflammatory and immunosuppressive effects of UVB, topical application of green or white tea has been shown to completely prevent the formation of 8-OH-dG adducts in human skin [21]. The reduction of DNA damage, aberrant cell signaling, inflammation, and immunosup‐ pression are mechanisms exhibited by teas and tea extracts that contribute to their anti-cancer properties.

Photooxidative damage occurs when the antioxidant defense mechanisms of the skin are overwhelmed by UV-induced ROS, particularly from UVA. ROS that contribute to photocar‐ cinogenesis and photoaging include singlet oxygen, superoxide radical anion, hydroxyl radical, perhydroxyl radical, and hydrogen peroxide [10, 13, 37-39]. Endogenous antioxidants that scavenge for ROS include superoxide dismutase, glutathione peroxidase, ascorbate, alpha-lipoic acid, and catalase [16]. Excessive ROS generated during UV exposure depletes endogenous antioxidants, and causes a state of oxidative stress in cells that can damage cellular proteins, lipids, DNA, trigger apoptosis, and contribute to photocarcinogenesis [14]. Incorpo‐ rating antioxidants into sunscreens can ameliorate UV-induced tissue damage and promote

Human studies with antioxidant supplementation to sunscreens have been successful at demonstrating the benefits of including antioxidants in the formulation. In a human study, the combination of a several antioxidants, including ascorbyl phosphate, tocopherol acetate, *Echinacea pallida* extract, chamomile extract, and caffeine, with sunscreen best protected the skin compared to sunscreen alone after repetitive irradiation with solar simulated UVR [40]. A significant inhibition of UVR-induced melanin synthesis was observed in the presence of antioxidants alone. There was a synergy between the antioxidants and broad spectrum sunscreen, making the combination more protective than either the antioxidants or sunscreen alone. The antioxidant alone was able to prevent hyperproliferation and thickening of the epidermis that is a typical biological response to chronic UVR exposure. UV-induction of cytokeratin 16 and MMP9 was also suppressed by antioxidant cocktail and sunscreen combi‐ nation [40]. In another study using a similar combination of antioxidants, sunscreen with antioxidants or sunscreen alone were equally able to protect against immunosuppression as measured by immunohistochemical staining for Langerhans cells. Less induction of tissue remodeling protein MMP1 was observed with the sunscreen plus antioxidant formulation [13]. Taken together, this data demonstrates additive or synergistic effects of antioxidants for

Tea (*Camellia sinensis*) drinking has been associated with health in many cultures. Green tea consumption has been associated with reduced cancer risk, including SCC [17]. It has been demonstrated in mouse skin tumor models that green tea inhibits photocarcinogenesis [37]. Epigallocatechin-3-gallate (EGCG) makes up approximately 40% of all the polyphenols found in green tea, and it is believed to be the main polyphenol responsible for the beneficial health effects of green tea [12, 37]. White and black teas also have protective effects. Theaflavins, the polyphenols found in black tea, can inhibit the UVB-induced activation of cell signaling through AP-1, MAPK, and extracellular matrix receptor-activated kinase [17]. Topical application of white or green teas have been shown to protect against the loss of Langerhans cells after solar simulated UVR exposure in both human subjects and in an *ex vivo* skin explant model [21]. In another human study, EGCG inhibited UVB-induced erythema and inflamma‐ tion. Fewer leukocytes infiltrated the skin when EGCG was applied prior to irradiation with UVB, and less prostanoids were synthesized [37]. In addition to being able to suppress the

DNA repair [13].

218 Highlights in Skin Cancer

photoprotection.

**5.1. Green tea**

The amount of pre-treatment time and concentration of green tea polyphenols required to obtain optimal protection on human skin was elucidated in a study by Elmets et.al. In this study, skin on the back of six human subjects was pre-treated for 30 minutes with 0.25-10% solutions of green tea polyphenols. The skin was then irradiated with a solar simulator at twice the individual's minimal erythema dose (MED). At 24, 48, and 72 hours post-exposure erythema was quantified with a chromameter and biopsies were taken from the exposed sites. Erythema was found to be reduced in a dose-dependent manner at all time points and with all doses of green tea polyphenol that were used (figure 1). Pre-treatment with the polyphenols was noted to work best when applied immediately before exposure as opposed to several hours before exposure. Analysis of the biopsies revealed a 66% reduction in the number of sunburn cells, significantly less Langerhans cell migration at 4 days post-exposure, and a 55% reduction in DNA lesions. Subjects were also irradiated with 135 J/cm2 UVA only, and pre-treatment with 5% green tea polyphenols significantly protected against UVA-induced erythema in that experiment [9]. The results of this study indicate that the use of green tea polyphenols is most effective at protecting the skin from UVR when used at a concentration of 0.25% or greater, with the greatest protection observed when applying a 10% solution 30 minutes before irradiation. Adding green tea polyphenols to sunscreens could enhance broad spectrum protection since they have been demonstrated to reduce UVA-induced erythema.

**Figure 1.** Effect of green tea polyphenols (GTP) on the erythema response evoked by 2-MED solar simulated radiation. Data represent the mean ± standard error of the mean erythema index at 24, 48, and 72 hours after irradiation with a solar simulator. Measurements were made with a chromameter on 6 volunteers. Areas of skin were pretreated with indicated concentration of an extract of green tea (GTE) 30 minutes before UV exposure. Reprinted from Cutaneous photoprotection from ultraviolet injury by green tea polyphenols, Journal of the American Academy of Dermatology, 44(3):425-32, Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H, (2001) with permission from Elsevier.

In a parallel experiment, Elmets et.al tested separate green tea polyphenols for ability to inhibit erythema on human subjects irradiated with solar simulated UVR. The polyphenols tested were 5% solutions of EGCG, epicatechin (EC), epigallocatechin (EGC), or epicatechin-3-gallate (ECG). EC and EGC were not effective at inhibiting erythema, but EGCG and ECG were. The authors were intrigued by this finding because EGCG and ECG both contain a galloyl group at the 3 position, and this common structure between them could be the source of their effectiveness compared to the other polyphenols that were tested [9]. These results confirmed that EGCG is one of the polyphenols that contributes the most to the photoprotective effects of green tea.

**5.5. Chocolate**

**5.6. Beta-carotene**

Fresh cocoa beans contain high levels of polyphenols that are potent antioxidants. Most commercially available chocolate does not contain high antioxidants because conventional chocolate making diminishes antioxidant capacity. Chocolate that is specially prepared to retain high amounts of active flavanols can increase the MED in human subjects who ate it

Skin Cancer Prevention Strategies http://dx.doi.org/10.5772/55241 221

β-carotene is a fat soluble antioxidant carotenoid found in many plants, and gives orange color to many fruits and vegetables, such as carrots and yams. It is a precursor to vitamin A, also known as provitamin A [43]. The effectiveness of β-carotene as a systemic photoprotectant in humans is dependent upon the dose and the duration of consumption before irradiation with UVR. Reports suggest that in order for β-carotene pre-treatment to be effective it should be consumed at a dose of 20 mg per day for at least 10 weeks, and moderate intake is insufficient to achieve photoprotection [8]. Meta-analysis of seven human studies on sunburn protection and β-carotene arrived at the same conclusion, and added that the mean photoprotection provided by β-carotene increases for each month beyond 10 weeks of consistent consumption,

every day for 12 weeks compared to subjects who ate conventional chocolate [42].

and β-carotene can provide system photoprotection with a maximal SFP of 4. [43].

for smokers, as it has been shown to increase lung cancer risk [44].

has been reported to prevent immunosuppression [16].

**5.7. Vitamin C and Vitamin E**

While dietary supplementation with β-carotene protects against sunburn, it is not effective for preventing skin cancer when used alone. A data review of randomized control studies did not find a positive association between oral β-carotene supplementation and the prevention of melanoma or non-melanoma [44]. β-carotene supplementation could be used in combination with other photoprotective methods to reduce sunburn. However, dietary supplementation with β-carotene should be done with caution because at high levels it can create a prooxidative state that is damaging to the body. Consuming high amounts of β-carotene is not suggested

Vitamin C (ascorbic acid) and vitamin E (α-tocopherol) are photoprotective antioxidants that can be combined with other antioxidants like β-carotene or added into sunscreen to protect the skin from UVR. Vitamin E is a potent inhibitor of lipid peroxidation, and it is typically found in plant derived oils. Vitamin C has functions as a reducing agent and is an essential vitamin for humans. Vitamins C and E have a synergistic relationship; vitamin C can regenerate oxidized vitamin E at the cell membrane [38, 39]. Oral administration of 200mg/day vitamin C and 1000IU/day of vitamin E for eight days in humans reduces sensitivity to solar simulated UVR as observed by higher MED in subjects [38]. The combination of vitamin E with β-carotene has been shown to suppress UVR-induced erythema better than β-carotene alone when administered orally for 12 weeks [39]. Topical application of vitamin E onto hairless mice prior to irradiation with solar simulated UV

### **5.2. Resveratrol**

Resveratrol is a chemopreventive phytochemical found in grape skin and seeds, red wine, peanuts, and fruits. Topical application of resveratrol in hairless mice has been shown to reduce signs of oxidative stress and inflammation induced by UVB exposure [12]. Daily topical application of resveratrol in humans prior to irradiation with solar simulated UVR for four consecutive days provided significant protection against erythema, melanin synthesis, tanning, and sunburn cell formation compared to unprotected skin [10].

#### **5.3. Pomegranate**

Pomegranate is known for its strong anti-inflammatory, antioxidant, anti-proliferative, and anti-tumorigenic properties. Anthocyanidins and hydrolysable tannins are polyphenols found in pomegranate. In an animal study, hairless mice were irradiated with 180 mJ/cm2 UVB after consuming 0.2% (wt/vol) pomegranate extract for two weeks. Analysis of skin biopsies taken from the mice revealed that pomegranate consumption resulted in the inhibition of UVBinduced skin edema, cell proliferation, infiltration of leukocytes, NFκB activation, COX-2 expression, CPDs, 8-OH-dG, and generation of hydrogen peroxide and lipid peroxidation [11]. These results suggest that regular consumption of pomegranate could provide systemic protection from UVB.

#### **5.4. Lycopene**

Lycopene is a carotenoid found in tomatoes, red bell peppers, watermelon and other redcolored fruits and vegetables. Lycopene consumption is believed to aid in the prevention of cardiovascular disease, diabetes, and cancer because of its strong antioxidant property. The bioavailability of lycopene is greater in cooked and processed foods than from fresh fruits. It has been recognized as one of the most powerful quenchers of singlet oxygen of all the carotenoids [41]. Dietary intake of lycopene or foods rich in lycopene can provide systemic photoprotection. Daily consumption of 55 grams of tomato paste with olive oil for 12 weeks protected individuals from solar simulated UVR-induced mitochondrial DNA damage compared to individuals who ate olive oil alone. Less induction of matrix metalloproteinases was also found, and the skin of the group that ate tomato paste tended to have a higher MED than the group that did not [41]. In another human study, individuals that consumed lycopene for 10-12 weeks developed about 40% less erythema than those that did not [8].

#### **5.5. Chocolate**

were 5% solutions of EGCG, epicatechin (EC), epigallocatechin (EGC), or epicatechin-3-gallate (ECG). EC and EGC were not effective at inhibiting erythema, but EGCG and ECG were. The authors were intrigued by this finding because EGCG and ECG both contain a galloyl group at the 3 position, and this common structure between them could be the source of their effectiveness compared to the other polyphenols that were tested [9]. These results confirmed that EGCG is one of the polyphenols that contributes the most to the photoprotective effects

Resveratrol is a chemopreventive phytochemical found in grape skin and seeds, red wine, peanuts, and fruits. Topical application of resveratrol in hairless mice has been shown to reduce signs of oxidative stress and inflammation induced by UVB exposure [12]. Daily topical application of resveratrol in humans prior to irradiation with solar simulated UVR for four consecutive days provided significant protection against erythema, melanin synthesis,

Pomegranate is known for its strong anti-inflammatory, antioxidant, anti-proliferative, and anti-tumorigenic properties. Anthocyanidins and hydrolysable tannins are polyphenols found

consuming 0.2% (wt/vol) pomegranate extract for two weeks. Analysis of skin biopsies taken from the mice revealed that pomegranate consumption resulted in the inhibition of UVBinduced skin edema, cell proliferation, infiltration of leukocytes, NFκB activation, COX-2 expression, CPDs, 8-OH-dG, and generation of hydrogen peroxide and lipid peroxidation [11]. These results suggest that regular consumption of pomegranate could provide systemic

Lycopene is a carotenoid found in tomatoes, red bell peppers, watermelon and other redcolored fruits and vegetables. Lycopene consumption is believed to aid in the prevention of cardiovascular disease, diabetes, and cancer because of its strong antioxidant property. The bioavailability of lycopene is greater in cooked and processed foods than from fresh fruits. It has been recognized as one of the most powerful quenchers of singlet oxygen of all the carotenoids [41]. Dietary intake of lycopene or foods rich in lycopene can provide systemic photoprotection. Daily consumption of 55 grams of tomato paste with olive oil for 12 weeks protected individuals from solar simulated UVR-induced mitochondrial DNA damage compared to individuals who ate olive oil alone. Less induction of matrix metalloproteinases was also found, and the skin of the group that ate tomato paste tended to have a higher MED than the group that did not [41]. In another human study, individuals that consumed lycopene

for 10-12 weeks developed about 40% less erythema than those that did not [8].

UVB after

in pomegranate. In an animal study, hairless mice were irradiated with 180 mJ/cm2

tanning, and sunburn cell formation compared to unprotected skin [10].

of green tea.

220 Highlights in Skin Cancer

**5.2. Resveratrol**

**5.3. Pomegranate**

protection from UVB.

**5.4. Lycopene**

Fresh cocoa beans contain high levels of polyphenols that are potent antioxidants. Most commercially available chocolate does not contain high antioxidants because conventional chocolate making diminishes antioxidant capacity. Chocolate that is specially prepared to retain high amounts of active flavanols can increase the MED in human subjects who ate it every day for 12 weeks compared to subjects who ate conventional chocolate [42].

#### **5.6. Beta-carotene**

β-carotene is a fat soluble antioxidant carotenoid found in many plants, and gives orange color to many fruits and vegetables, such as carrots and yams. It is a precursor to vitamin A, also known as provitamin A [43]. The effectiveness of β-carotene as a systemic photoprotectant in humans is dependent upon the dose and the duration of consumption before irradiation with UVR. Reports suggest that in order for β-carotene pre-treatment to be effective it should be consumed at a dose of 20 mg per day for at least 10 weeks, and moderate intake is insufficient to achieve photoprotection [8]. Meta-analysis of seven human studies on sunburn protection and β-carotene arrived at the same conclusion, and added that the mean photoprotection provided by β-carotene increases for each month beyond 10 weeks of consistent consumption, and β-carotene can provide system photoprotection with a maximal SFP of 4. [43].

While dietary supplementation with β-carotene protects against sunburn, it is not effective for preventing skin cancer when used alone. A data review of randomized control studies did not find a positive association between oral β-carotene supplementation and the prevention of melanoma or non-melanoma [44]. β-carotene supplementation could be used in combination with other photoprotective methods to reduce sunburn. However, dietary supplementation with β-carotene should be done with caution because at high levels it can create a prooxidative state that is damaging to the body. Consuming high amounts of β-carotene is not suggested for smokers, as it has been shown to increase lung cancer risk [44].

#### **5.7. Vitamin C and Vitamin E**

Vitamin C (ascorbic acid) and vitamin E (α-tocopherol) are photoprotective antioxidants that can be combined with other antioxidants like β-carotene or added into sunscreen to protect the skin from UVR. Vitamin E is a potent inhibitor of lipid peroxidation, and it is typically found in plant derived oils. Vitamin C has functions as a reducing agent and is an essential vitamin for humans. Vitamins C and E have a synergistic relationship; vitamin C can regenerate oxidized vitamin E at the cell membrane [38, 39]. Oral administration of 200mg/day vitamin C and 1000IU/day of vitamin E for eight days in humans reduces sensitivity to solar simulated UVR as observed by higher MED in subjects [38]. The combination of vitamin E with β-carotene has been shown to suppress UVR-induced erythema better than β-carotene alone when administered orally for 12 weeks [39]. Topical application of vitamin E onto hairless mice prior to irradiation with solar simulated UV has been reported to prevent immunosuppression [16].

#### **5.8. Polypodium leucotomos**

An organic extract of the tropical South American fern *Polypodium leucotomos*, given the commercial name "Fernblock", can be used orally or topically to protect the skin from solar UVR. This extract protects against the genotoxic effects of UVB by preventing the forma‐ tion of CPDs, 8-OH-dG, and mitochondrial DNA damage. It induces the p53 tumor suppressor protein. The extract prevents UVR-induced inflammation through the inhibi‐ tion of pro-inflammatory molecules (tumor necrosis factor alpha and nitric oxide syn‐ thase), COX-2, apoptosis of keratinocytes and fibroblasts, and general reduction of erythema and sunburn. One component of Fernblock, caffeic acid, prevents oxidative stress by inhibiting the formation of peroxide and nitric oxide upon exposure to UVR. Fernblock also prevents the immunosuppressive effects of UVR by suppressing the migration of Langer‐ hans cells and activation of T helper type 2 cells. Remodeling of the dermal extracellular matrix by matrix metalloproteinase 3 is inhibited by the extract, and both collagen and elastin proteins are up regulated indicating that the extract may also fight photoaging. Topical application of the extract on hairless mice was reported to block UVB-induced skin tumor formation. All of these positive protective effects make Fernblock a potentially powerful photocarcinogenesis protective agent [14].

skin modifies the vitamin into its active form called calcitriol (25(OH)2D3) [49]. Calcitriol binds to the nuclear vitamin D receptor (VDR), which then forms a heterodimer with the retinoid-X receptor and becomes a transcription factor that regulates the expression of cell cycle, cell

Skin Cancer Prevention Strategies http://dx.doi.org/10.5772/55241 223

**Figure 2.** Vitamin D synthesis and biological effects. Reprinted by permission of Macmillan Publishers Ltd: Nature Re‐ views Cancer, Deeb KK, Trump DL, Johnson CS, Vitamin D signaling pathways in cancer: potential for anticancer thera‐

There is contradictory evidence about whether vitamin D protects against cancer. A study conducted by the National Institutes of Health did not find a correlation between vitamin D levels and internal cancers [49]. Other studies have found that vitamin D can reduce the risk of internal cancers, particularly prostate and colorectal cancer [48]. It was reported in an observational study that individuals with the lowest serum levels of 25(OH)D3 had a 26% higher mortality rate when compared to those with higher vitamin D levels [45]. It is hypothe‐ sized that high blood levels of 25(OH)D3 result in higher levels of calcitriol that regulates cell proliferation. A number of cells in the body, including breast, colon, and skin, have the

proliferation, and apoptosis genes [2].

peutics, 07(9):648-700 (2007).

#### **6. Vitamin D**

Vitamin D is important for bone health, intestinal uptake of calcium and phosphate, and regulation of calcium and phosphate levels in the blood [2, 4]. Vitamin D is associated with the prevention of autoimmune disease, cardiovascular disease, and believed to have antiinflammatory and anti-proliferative effects [45, 46]. The current recommended daily allowance for vitamin D is 400 IU for infants under 1 year old, 600 IU for persons 1-70 years old, and 800 IU for persons older than 70 years [47]. People who have vitamin D insufficiency are recom‐ mended to take 1,000 IU of vitamin D daily [48].

Lack of vitamin D results in poor enteral absorption of calcium that causes decreased blood levels of ionized calcium. This decrease promotes the breakdown of bone by osteoclasts to release calcium. By this mechanism, vitamin D insufficiency in adults can lead to osteoporosis. Childhood vitamin D deficiency causes Rickets disease. During the late 1800s to early 1900s Rickets disease afflicted more than 80% of North American and European children who lived in industrialized cities. After it was learned that a deficiency in vitamin D was to blame for the bone deformities caused by this disease, increasing exposure to sunlight and fortification of milk with vitamin D in the 1930s helped to reduce the incidence of Rickets in the United States [46, 47]. In addition to dietary sources, vitamin D can be obtained by cutaneous synthesis upon exposure to sunlight (figure 2). Upon irradiation with UVB, 7-dehydrocholsterol (provitamin D) in the skin is converted into pre-cholecalciferol (previtamin D3). Pre-cholecalciferol undergoes a spontaneous isomerization into cholecalciferol (vitamin D3). Vitamin D-binding protein (DBP) transports vitamin D3 to the liver where it is hydroxylated by cytochrome p450 27A1 into 25-hydroxyvitamin D (25(OH)D3) [2]. Further hydroxylation in the kidney or at the skin modifies the vitamin into its active form called calcitriol (25(OH)2D3) [49]. Calcitriol binds to the nuclear vitamin D receptor (VDR), which then forms a heterodimer with the retinoid-X receptor and becomes a transcription factor that regulates the expression of cell cycle, cell proliferation, and apoptosis genes [2].

**5.8. Polypodium leucotomos**

222 Highlights in Skin Cancer

**6. Vitamin D**

powerful photocarcinogenesis protective agent [14].

mended to take 1,000 IU of vitamin D daily [48].

An organic extract of the tropical South American fern *Polypodium leucotomos*, given the commercial name "Fernblock", can be used orally or topically to protect the skin from solar UVR. This extract protects against the genotoxic effects of UVB by preventing the forma‐ tion of CPDs, 8-OH-dG, and mitochondrial DNA damage. It induces the p53 tumor suppressor protein. The extract prevents UVR-induced inflammation through the inhibi‐ tion of pro-inflammatory molecules (tumor necrosis factor alpha and nitric oxide syn‐ thase), COX-2, apoptosis of keratinocytes and fibroblasts, and general reduction of erythema and sunburn. One component of Fernblock, caffeic acid, prevents oxidative stress by inhibiting the formation of peroxide and nitric oxide upon exposure to UVR. Fernblock also prevents the immunosuppressive effects of UVR by suppressing the migration of Langer‐ hans cells and activation of T helper type 2 cells. Remodeling of the dermal extracellular matrix by matrix metalloproteinase 3 is inhibited by the extract, and both collagen and elastin proteins are up regulated indicating that the extract may also fight photoaging. Topical application of the extract on hairless mice was reported to block UVB-induced skin tumor formation. All of these positive protective effects make Fernblock a potentially

Vitamin D is important for bone health, intestinal uptake of calcium and phosphate, and regulation of calcium and phosphate levels in the blood [2, 4]. Vitamin D is associated with the prevention of autoimmune disease, cardiovascular disease, and believed to have antiinflammatory and anti-proliferative effects [45, 46]. The current recommended daily allowance for vitamin D is 400 IU for infants under 1 year old, 600 IU for persons 1-70 years old, and 800 IU for persons older than 70 years [47]. People who have vitamin D insufficiency are recom‐

Lack of vitamin D results in poor enteral absorption of calcium that causes decreased blood levels of ionized calcium. This decrease promotes the breakdown of bone by osteoclasts to release calcium. By this mechanism, vitamin D insufficiency in adults can lead to osteoporosis. Childhood vitamin D deficiency causes Rickets disease. During the late 1800s to early 1900s Rickets disease afflicted more than 80% of North American and European children who lived in industrialized cities. After it was learned that a deficiency in vitamin D was to blame for the bone deformities caused by this disease, increasing exposure to sunlight and fortification of milk with vitamin D in the 1930s helped to reduce the incidence of Rickets in the United States [46, 47]. In addition to dietary sources, vitamin D can be obtained by cutaneous synthesis upon exposure to sunlight (figure 2). Upon irradiation with UVB, 7-dehydrocholsterol (provitamin D) in the skin is converted into pre-cholecalciferol (previtamin D3). Pre-cholecalciferol undergoes a spontaneous isomerization into cholecalciferol (vitamin D3). Vitamin D-binding protein (DBP) transports vitamin D3 to the liver where it is hydroxylated by cytochrome p450 27A1 into 25-hydroxyvitamin D (25(OH)D3) [2]. Further hydroxylation in the kidney or at the

**Figure 2.** Vitamin D synthesis and biological effects. Reprinted by permission of Macmillan Publishers Ltd: Nature Re‐ views Cancer, Deeb KK, Trump DL, Johnson CS, Vitamin D signaling pathways in cancer: potential for anticancer thera‐ peutics, 07(9):648-700 (2007).

There is contradictory evidence about whether vitamin D protects against cancer. A study conducted by the National Institutes of Health did not find a correlation between vitamin D levels and internal cancers [49]. Other studies have found that vitamin D can reduce the risk of internal cancers, particularly prostate and colorectal cancer [48]. It was reported in an observational study that individuals with the lowest serum levels of 25(OH)D3 had a 26% higher mortality rate when compared to those with higher vitamin D levels [45]. It is hypothe‐ sized that high blood levels of 25(OH)D3 result in higher levels of calcitriol that regulates cell proliferation. A number of cells in the body, including breast, colon, and skin, have the enzymes required to make calcitriol. It is suggested that when vitamin D levels are high local production of calcitriol keeps cell proliferation in check and reduces risk of carcinogenesis [46]. Thus, it is speculated that vitamin D production in the skin is protective and sunscreen use diminishes protection by inhibiting vitamin D synthesis.

practiced daily is not widely followed, as evident by the fact that people are more likely to follow skin protection methods while on vacation or at the beach than when participating in other outdoor recreational activities [19]. Intentional unprotected sun exposure for cosmetic purposes is prominent in young adults because of the perception that tanned skin is more attractive [48]. About 50% of people in the U.S. between the ages of 18 and 24 years old report having a sunburn in the last year, compared to about 35% of people over the age of 25 who reported having a sunburn in the last year [25]. This is coincides with the tendency for young people to expose themselves to solar and artificial UVR for tanning. Over one million people go to tanning salons on an average day in the United States [34], and most are under the age of 25 [25]. This risky behavior may contribute to melanoma being the second most common cancer in young adults between the ages of 15 and 29 years old [4]. In 2004, it was found that 69% of youths between the ages of 11 and 18 reported in a cross-sectional study survey that they had been sunburned that summer [19]. Summertime sunburns should not be taken lightly or treated as a normal occurrence. The risk of developing melanoma more than doubles for individuals who report having five or more severe sunburns during adolescence [19]. A study by the University of Miami on sun protection behavior in high school students found that white-Hispanics were not likely to use sunscreens, more than twice as likely to go tanning, and generally did not believe that they had a risk of getting skin cancer compared to white non-Hispanics [23]. This is an example of the need to educate young adults and teenagers who

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Physicians play in important role in educating patients about sun protection. Primary care physicians should actively promote broad spectrum sunscreen use, and review proper application techniques with patients to reduce sunburn. They should educate patients about the use of sunscreen as an adjunct to the other sun protection methods, and warn patients not to use sunscreen as a tool for prolonging sun exposure because that behavior increases the risk of sunburn [19, 26]. They could point patients towards many informative public education websites about sun protection and skin cancer prevention that are available from government

Skin cancer prevention awareness is spreading with the help of government organizations, such as the National Institutes of Health and National Council on Skin Cancer. Increasing numbers of advertisements for skin cancer prevention are seen on television, heard on the radio, and posted in public places. Major awareness advocates, programs, and campaigns include the SunSmart campaign in Australia and the United Kingdom, the European Skin Cancer Foundation, the SunAWARE non-profit educational organization in the U.S., the USEPA SunWise program, American Academy of Dermatology, the Skin Cancer Foundation in the U.S., and the American Cancer Society. These groups and programs aim to educate the public about skin cancer and encourage multi-step behavioral modifications to reduce the risk of developing skin cancer. The SunAWARE organization uses AWARE as an easy acronym to help people remember the steps of sun protection (figure 3). Skin cancer incidence rates have been stabilizing when compared to the rapid increases seen before the rise in establishment of government-sponsored sun protection programs [19]. The message is starting to be heard, as evident by an overall increase in adult sunscreen use between 2005 and 2010 [25]. Sun safety

are unaware of the health risks associated with sun exposure.

and non-profit organizations.

There is almost no evidence supporting the idea that the vitamin D deficiency epidemic is correlated to the overuse of sunscreen [48]. Sunscreen use may diminish photosynthesis of vitamin D, but it is not necessary or recommended to obtain vitamin D from intentional sun exposure. To maximize cutaneous synthesis of vitamin D, individuals would have to expose themselves to sunlight for the amount of time required to achieve one third of their MED, meaning the skin would incur damage to make vitamin D. Incidental sun exposure for 10-20 minutes on skin protected with SPF 15 or greater sunscreen could maximize cutaneous vitamin D synthesis while protecting the skin because sunscreen does not block all UV [48]. While some people find the idea of synthesizing their own vitamin D through intentional sun exposure holistic and appealing, the better option is to continue protecting skin from solar UVR with sunscreen and protective clothing, and to obtain vitamin D from dietary sources and incidental protected sun exposure. A variety of foods including milk, bread, cereal, yogurt, and multi‐ vitamins are fortified with vitamin D in the United States and are good alternatives to intentional exposure to sunlight. The use of indoor tanning beds to increase vitamin D levels is not advised [4, 48, 50].

Populations susceptible to vitamin D deficiency are the eldery, people with darkly pigmented skin, breastfed infants, and obese people. The suggestion that elderly and darkly pigmented populations intentionally expose themselves to UVR is not a good solution because these susceptible populations generally have poor cutaneous vitamin D synthesis. The ability to photosynthesize vitamin D in the skin decreases with age because there is less 7-dehydrocho‐ lesterol in the skin. People with darkly pigmented skin have increased melanin in the epider‐ mis that inhibits cutaneous vitamin D synthesis [2, 46, 48]. It does not make sense for the elderly or people with darkly pigmented skin to intentionally expose themselves to sunlight to make vitamin D since the process is inefficient in their skin. Rather, they should take dietary supplements and incorporate foods fortified with vitamin D. Obesity is also a risk factor for deficiency of vitamin D. Vitamin D3 is stored deep in the body fat of obese individuals and is not readily bioavailable to them during winter months, so they can only mobilize about half the amount of vitamin D3 as persons with healthy weights [46]. Human breast milk contains less than 78 IU vitamin D per liter so it is recommended that infants also receive vitamin D supplementation [47]. Infants should not be exposed to solar UV to increase vitamin D synthesis [2]. Dietary supplementation with vitamin D is the best option for all people, especially those with reduced ability to synthesize and maintain vitamin D levels in their body.
