Botanicals in Dermatology: An Evidence-based Review

Juliane Reuter; Irmgard Merfort; Christoph M. Schempp

Disclosures

Am J Clin Dermatol. 2010;11(4):247-267. 

In This Article

4. UV-induced Skin Damage and Non-melanoma Skin Cancer

Photoaging and the development of skin cancer are of increasing importance since changes in lifestyle have led to a significant increase in the individual cumulative UV doses. This trend is likely to continue in the future. Therefore, the adverse effects of UV irradiation on the skin have become a major human health concern. New prevention strategies have to be developed to reduce UV exposure and delay photoaging processes, aiming at reducing the incidence of skin cancer. Within this context, topically as well as orally administered botanicals are of interest. Basically, all botanicals that have been shown to possess antioxidant properties can be considered to be beneficial in the prevention of photocarcinogenesis.[83] It is suggested that routine consumption of those botanicals may provide protection against many harmful effects of UV irradiation. In combination with sunscreens or skin care lotions they may provide an effective strategy for reducingUV-induced skin diseases.[83]

UV-induced skin damage can be classified into three clinical stages. The acute stage of skin damage is sunburn, characterized by clinical signs of inflammation such as erythema, pain, and swelling, and histologically by sunburn cells. In chronically UV-exposed skin the elastic and collagenous fibers are rarified and precancerous skin conditions such as actinic keratoses are present. Finally, in long-term, UV-exposed skin, non-melanoma skin cancer such as squamous cell carcinoma and basal cell carcinoma may eventually develop. The mechanisms, prevention, and therapy have been reviewed extensively by Yaar and Gilchrest.[84] Various botanicals have been reported to help prevent photocarcinogenesis by displaying anticarcinogenic and antimutagenic activities because of their antioxidative and anti-inflammatory properties.[85]

4.1 Protection from Acute Erythema

The extract of the tropical cabbage palm fern (CPF) [Phlebodiumaureum or Polypodium leucotomos] is a plant-derived product that has been studied in vitro as well as in vivo.Aclinical study in 21 healthy subjects exposed to UV irradiation before and after administration of CPF demonstrated that CPF, orally administered as well as topically used, displays significant photoprotective properties by preventing sunburn and psoralen-induced phototoxic reactions, and immunohistochemically revealed photoprotection of epidermal Langerhans cells[86] [LOE-B]. In a recent small study with ten subjects, it was shown that CPF is an effective protector against PUVA-induced skin phototoxicity and protects the skin from damaging effects of PUVA as evidenced by histology[87] [LOE-C]. Another trial with nine volunteers assessed erythema reactions afterUVirradiation without CPF and after oral administration of CPF. The clinical and histologic results revealed that the oral CPF extract decreased UV-induced skin damage[88] [LOE-C]. One possible molecular mechanism for this protection seems to be the inhibition of UV-induced photoisomerization of transurocanic acid, a common photoreceptor located in the stratum corneum. The CPF extract also blocks its photodecomposition in the presence of oxidizing reagents such as hydrogen peroxide and titanium dioxide. Additionally, it was shown that CPF protects human fibroblasts from UV-induced death in vitro[89] [LOE-D].

Topical application of anti-inflammatory plant extracts immediately after irradiation can reduce symptoms of sunburn. In 40 human volunteers, an ointment containing 2% extract of sage (S. officinalis) rich in phenolic diterpenes inhibited UV-induced erythema in vivo to a similar extent as did hydrocortisone 1%[90] [LOE-A]. Anti-inflammatory efficacy in a UVB erythema test could also be demonstrated for a topical preparation containing 10% of a distillate from witch hazel (H. virginiana)[91] [LOE-A].

Dietary supplements that provide moderate protection against UV-induced erythema are carotenoids such as β-carotene or lycopene. In a placebo-controlled, parallel-group study design, 36 volunteers received β-carotene, a carotenoid mix, or placebo for 12 weeks.[92] Carotenoid levels in serum and skin of the palm, as well as erythema intensity before and 24 hours after irradiation with a solar light simulator were measured at baseline and after 6 and 12 weeks of treatment. The results showed that long-term supplementation for 12 weeks with a carotenoid mix ameliorated UV-induced erythema in humans. The effect was comparable to a daily supplementation with 24 mg of β-carotene alone[92] [LOE-A]. Within a study of 36 healthy volunteers, the photoprotective effect of synthetic lycopene in comparison with a tomato extract and a drink containing the tomato extract in a solubilized form was evaluated.[93] With these different carotenoid sources, the volunteers ingested similar amounts of lycopene (about 10mg/day). After 12 weeks of supplementation, significant increases in lycopene serum levels and total skin carotenoids were observed in all groups. The induced erythema at weeks 0, 4, and 12 was most decreased at week 12, with a protective effect most pronounced in the group consuming the solubilized tomato extract (48% after 12 weeks)[93] [LOE-B].

4.2 Effects of Long-term Oral Administration on Skin Aging and Cancer Prevention

Green tea extract (manufactured from C. sinensis) with a high content of oligomeric proanthocyanidins is another UV damage-preventing agent. It mainly contains catechin and epicatechin derivatives, with epigallocatechin gallate being the most important compound. It is able to scavenge free radicals and acts as a potent antioxidant. The anticarcinogenic properties of green tea have been thoroughly investigated in vitro as well as in vivo. Recently, a review of numerous studies with green tea has concluded that both oral consumption and topical application of green tea protects against inflammation and chemical- and UV-induced carcinogenesis[94] [LOE-A]. Various cytokines involved in the inflammation process in the beginning of skin tumor development are inhibited by green tea extract. Moreover, biochemical markers of chemical carcinogenesis as well as UV-induced oxidative stress are counteracted by green tea extract. In addition, UV-induced immunosuppression is prevented by green tea[94] [LOE-D]. Also, it has been shown that green tea protects against PUVA-induced photochemical damage to the skin[95] [LOE-D]. The in vitro photoprotective effects of tea polyphenols and caffeine as a component of tea have recently been evaluated within some reviews[96–98] [LOE-D]. However, tea polyphenols have yet to be evaluated in clinical intervention trials in humans.

Black tea (fermented C. sinensis) may also play a role in UV protection and chemoprevention due to theaflavins[99] [LOE-D]. It has been shown that theaflavins are equally effective antioxidants as are catechins in green tea[100] [LOE-D].

The extract of the fruits of the coffee plant (Coffea arabica) has been shown to exhibit antioxidant activity mediated by potent antioxidant polyphenols, especially chlorogenic acid, condensed proanthocyanidins, quinic acid, and ferulic acid[101] [LOE-D]. Because of these antioxidants, the extract might be valuable for photoprotection and chemoprevention. In a clinical study, 30 patients with actinic damage of the skin used a skin care system containing this extract.[102] Twenty patients had full face application of the test product, and ten patients had half-side application with the other side covered with a placebo cream. Compared with placebo, the test cream was significantly superior in improving fine lines, wrinkles, pigmentation, and overall appearance[102] [LOE-A]. In a double-blind, non-controlled study, 24 women consumed either a high flavonol or low flavonol cocoa powder with epicatechin and catechin as major flavonol monomers, dissolved in water for 12 weeks.[103] UV-induced erythema was significantly decreased in the high flavonol group by 15%and 25%after 6 and 12 weeks of treatment, respectively, whereas no changes occurred in the low flavonol group. The ingestion of high flavonol cocoa led to an increase in blood flow of cutaneous and subcutaneous tissues and to an increase in skin density and skin hydration[103] [LOE-B].

Silymarin, a flavonoid complex isolated from the seeds of milk thistle (Silybum marianum), has been demonstrated to possess anti-inflammatory, antioxidative, and anticarcinogenic properties in vivo in animal models. Experimental data suggest that silymarin may be a promising chemopreventive and pharmacologically safe agent that can be exploited or tested against skin cancer in humans. Moreover, silymarin may favorably supplement sunscreen protection and provide additional antiphotocarcinogenic protection[104] [LOE-D].

Some other interesting dietary botanicals mainly containing antioxidant polyphenols appear as promising UV protection agents. Apigenin, a non-toxic botanical-derived flavonoid occurring in numerous herbs, fruits, and vegetables, curcumin obtained from the tumeric rhizome (Curcuma longa), proanthocyanidins from the seeds of grapes (V. vinifera), and resveratrol, a polyphenol found in numerous plant species including grapes, peanuts, fruits, red wine, and mulberries, have also been shown to possess the ability to protect the skin from harmful UV-induced effects by displaying antimutagenic, antioxidant, free radical scavenging, anti-inflammatory, and anticarcinogenic properties.[83] Other candidates are rosemary (R. officinalis) extract;[105] propolis,[106] a resinous material produced by honeybees from the bud and bark of certain plants and trees; red ginseng;[107] genistein, an isoflavone from soybeans;[108] and pomegranate (Punica granatum)[109] [all LOE-D]. It has also been shown that the pomegranate extract protects human immortalized HaCaT keratinocytes against UVB-induced oxidative stress and markers of photoaging, and might therefore be a useful supplement in skin care products[110] [LOE-D].

4.3 Therapeutic Treatment of Actinic Keratoses

Triterpenes extracted from the outer bark of birches contain more than 80% (volume in volume) betulin. This triterpene extract displays antiproliferative and pro-apoptotic effects in human squamous cell carcinoma cells in vitro.[111] In a prospective non-randomized study it has been shown that an ointment prepared from betulin is an effective treatment (79% responders) of actinic keratoses that represent in situ squamous cell carcinomas[112] [LOE-B]. These results were confirmed in a prospective, randomized study that compared the effect of betulin oleogel with cryosurgery and the combination of both in 45 patients with mild to moderate actinic keratoses[113] [LOE-B]. However, the high response rate of about 80% of the lesions needs to be confirmed in prospective, randomized, placebo-controlled studies with histologic examination.

An extract from the spurge Euphorbia peplus contains the diterpene ester ingenol mebutate that induces necrosis in tumor cells.Two randomized, double-blind, vehicle-controlled, phase II studies investigated the efficacy and safety of topical ingenol mebutate in actinic keratoses. In both studies, ingenol mebutate gel was highly effective and superior to vehicle, with only two or three applications[114,115] [LOE-A].

4.4 Summary

Many botanicals containing antioxidant flavonoids or other polyphenols can contribute to skin protection from UV irradiation and prevent sunburn, non-melanoma skin cancer, and early skin aging. Acute treatment before or after exposure to UV as well as long-term oral consumption or topical application seems appropriate, depending on the specific drug used. Classical nutrients like green and black tea, fruits, and vegetables contain these antioxidants, which also have beneficial effects in other fields of health protection, but for effective UV protection larger amounts than taken with normal nutrition seem necessary. Botanicals may be used externally as cosmetics or part of sun protection products or internally from food or food supplements. However, as shown previously, the LOE from clinical trials is poor and many more large-scale studies are needed to confirm UV protective effects for specific botanicals.

Betulin and ingenol mebutate appear to be interesting new potential options for therapy of precancerous skin modifications.

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