Chemoprevention of skin cancer through natural agents

To reduce the occurrence of skin cancers, the use of sunscreens and wearing protective clothing while in the sun are emphasized. These are important strategies, but sadly these efforts are only partially effective. Thus, the development of novel strategies to reduce the occurrence of skin cancer is a highly desirable goal. One attractive approach is through chemoprevention which is the use of naturally occurring agents or synthetic compounds to prevent the occurrence and subsequent development of cancer. The ideal chemopreventive agent(s) for use for prevention of skin cancer must be available in its active form with none or minimal toxicity and a known mechanism of action. A wide range of synthetic and naturally occurring agents have been identified as a rich source of skin cancer chemopreventive agents. For a variety of reasons, there is a greater emphasis on the use of naturally occurring compounds for skin cancer chemoprevention, and many such agents have found a place in skin care products. This review focuses on the use of naturally occurring agents present in the diet and beverages consumed by humans for the chemoprevention of skin cancer.     

Chemoprevention of nonmelanoma skin cancer

Skin cancer is the most common cancer in human beings. The increased incidence of skin cancer has brought much attention to the process by which these tumors develop and how they can be prevented. Efforts have been made to educate the public about the importance of protecting skin from excessive ultraviolet light. Despite this work, the incidence of skin cancer continues to increase. Available compounds may be useful in the chemoprevention of skin cancer. Chemoprevention is defined as oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer. Potential agents included are the retinoids; difluoromethylornithine; T4 endonuclease V; polyphenolic antioxidants, such as (-)-epigallocatechin gallate, found in green tea and grape seed extract; silymarin; isoflavone genestein; nonsteroidal anti-inflammatory drugs; curcumin; lycopene; vitamin E; beta-carotene; and selenium. Many of these agents are available over the counter as topical or oral preparations. LEARNING OBJECTIVE: At the conclusion of this activity, participants should be familiar with the chemopreventive agents and their efficacy, as well as any significant side effects associated with them.     

Nutrition and melanoma prevention

Melanoma has continued to rise in incidence despite public efforts to promote sun protection behaviors. Because sunscreen use does not completely prevent skin cancer induced by ultraviolet radiation, additional chemopreventive methods for protecting against and reversing the effects of ultraviolet photodamage need evaluation. Recent years have brought increased interest in dietary factors, such as natural botanicals and vitamins, for the prevention of melanoma. This contribution provides a narrative review of the relevant, nutrition-related literature found by searching the keywords "melanoma chemoprevention," "nutrition and melanoma," "dietary botanicals and melanoma prevention," "green tea and melanoma," "vitamin D and melanoma," and "vitamin E and melanoma" in the PubMed database. Although randomized controlled trials of humans are lacking, basic science and epidemiologic studies show promising benefits of many natural products in chemoprevention for melanoma. Future studies, hopefully, will yield concrete answers and clarify the role of commonly available dietary nutrients in melanoma chemoprevention.     

Green tea and skin

OBJECTIVE: To discuss the current knowledge of polyphenolic compounds present in green tea as anti-inflammatory, antioxidant, and anticarcinogenic in skin. DATA SOURCES: References identified from bibliographies of pertinent articles, including our work in related fields. STUDY SELECTION AND DATA EXTRACTION: Articles were selected based on the use of green tea or its polyphenolic constituents for prevention against inflammation and cancer in the skin. Also discussed is the possible use of green tea to treat various inflammatory dermatoses. DATA SYNTHESIS: The polyphenolic compounds from green tea were tested against chemical carcinogenesis and photocarcinogenesis in murine skin. These green tea polyphenols were found to afford protection against chemical carcinogenesis as well as photocarcinogenesis in mouse skin. A few experimental studies were conducted in human skin in our laboratory. Analysis of published studies demonstrates that green tea polyphenols have anti-inflammatory and anticarcinogenic properties. These effects appear to correlate with antioxidant properties of green tea polyphenols. CONCLUSIONS: The outcome of the several experimental studies suggests that green tea possess anti-inflammatory and anticarcinogenic potential, which can be exploited against a variety of skin disorders. Although more clinical studies are needed, supplementation of skin care products with green tea may have a profound impact on various skin disorders in the years to come. Arch Dermatol. 2000;136:989-994     

Novel approaches to chemoprevention of skin cancer

Protection against sun-induced damage leading to photocarcinogenesis in skin is a highly desirable goal. Among various strategies, chemopreventive approaches utilizing non-toxic agents to prevent the occurrence of precancerous lesions or their surrogate markers are potentially attractive. Epidemiological and experimental studies provide evidence that some naturally occurring chemical agents in the human diet can diminish cancer risk. Aside from water, tea is the most common beverage consumed worldwide. Black tea accounts for nearly 80% of total tea production. Black tea and green tea are derived from the same plant, Camelia sinensis. Green tea contains monomeric polyphenols known as flavanols and black tea contains dimeric flavanols and polymeric polyphenols known as theaflavins (TFs) and thearubigins (TRs). Over the past fifteen years our laboratory has been exploring the feasibility of using tea and its constitutents as an approach to skin cancer prevention. We demonstrated that green tea, black tea and constituent polyphenols protect against chemical- and ultraviolet B (UVB)-induced carcinogenesis and reduce the growth of established tumors in skin. We have also shown the efficacy of green and black tea extracts against UVB and psoralen + ultraviolet A (PUVA)-induced early damage in skin. Although PUVA is highly effective in treating certain skin diseases, careful follow-up studies of cohorts of patients have shown that similar to UVB, PUVA treatment increases the risk for cutaneous squamous cell carcinoma and melanoma. We have found that oral administration of a standardized green tea extract (SGTE) prior to and during treatment of SKH-1 mice diminished PUVA-induced skin hyperplasia and hyperkeratosis. SGTE-treatment also inhibited PUVA-induced accumulation of c-fos and p53 proteins and epithelial hyperproliferation. Both topical application and oral administration of SGTE after PUVA-treatment reduced skin inflammation and cell hyperproliferation. Topical application of SGTE to human skin prior to PUVA-treatment inhibited the delayed skin inflammatory response. Similarly, oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic sub-fractions protect against UVB-induced erythema in SKH-1 mice. Furthermore, topical application of tea extracts to human volunteers protects against UVB-induced erythema. In summary, these studies indicate that tea extracts are effective in reducing UVB- and PUVA-mediated DNA damage, expression of early response genes and early inflammatory changes in skin. These studies verify a conceptual rationale for employing naturally occurring dietary constitutents as an approach to cancer chemoprevention.     

Botanical antioxidants in the prevention of photocarcinogenesis and photoaging

Exposure of the skin to ultraviolet (UV) radiation, particularly its UV-B component (280-320 nm), from the sun results in erythema, edema, hyperplasia, hyperpigmentation, sunburn cells, immunosuppression, photoaging, and skin cancer. Amongst these various adverse effects of UV-B radiation, skin cancer and photoaging are of great concern. More recent changes in lifestyle have led to a significant increase in the amount of UV-B radiation people receive leading to a surge in the incidence of skin cancer and photoaging. As these trends are likely to continue in the foreseeable future, the adverse effect of UV-B has become a major human health concern. Therefore, development of novel strategies to reduce the occurrence of skin cancer and delay the process of photoaging are highly desirable goals. One approach to reduce their occurrence is through photochemoprevention, which we define as the use of agents capable of ameliorating the adverse effects of UV-B on the skin. Photochemoprevention via use of botanical antioxidants, present in the common diet of human have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. This review will focus on the effects of selected botanical antioxidants in the prevention of photocarcinogenesis and photoaging.     

Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation in various skin diseases including, premature aging of the skin and melanoma and non-melanoma skin cancers. Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of these harmful events in the UV-exposed skin. A wide variety of polyphenols or phytochemicals, most of which are dietary supplements, have been reported to possess substantial skin photoprotective effects. This review article summarizes the photoprotective effects of some selected polyphenols, such as green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, on UV-induced skin inflammation, oxidative stress and DNA damage, etc., with a focus on mechanisms underlying the photoprotective effects of these polyphenols. The laboratory studies conducted in animal models suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.     

Chemoprevention of basal cell carcinomas in the ptc1+/- mouse--green and black tea

Skin cancers are a rising menace as their incidence increases, attributed in part to increasing ultraviolet radiation exposure. This increasing problem has stimulated efforts to devise useful preventive approaches. The uncertain efficacy of exhortations to avoid sun exposure and to use protective clothing and sunscreens to reduce damage when exposed argue for the development of an oral chemopreventive agent. Bickers and others have studied the effects and mechanisms of tea and of its putative active components on inhibition of skin cancer in experimental models. To continue this work, we have studied the effects of oral green tea and black tea on a new model of ultraviolet-induced skin carcinogenesis - the development of basal cell carcinomas in ptc1+/- mice. To our surprise, we have found that tea preparations which others have used to prevent squamous cell carcinoma formation in mice fail to inhibit basal cell carcinogenesis in our model, suggesting that prevention of this cancer may require special, tumor-specific approaches.     

Photochemoprevention by botanical antioxidants

The trend towards an increase in incidence and higher prevalence of skin cancer makes identification of effective chemopreventive agents an urgent priority. Excessive exposure to solar ultraviolet (UV) B radiation has been implicated as its main cause. Since these trends are likely to continue in the foreseeable future, the adverse effect of UVB has become a major human health concern. Therefore, the development of novel strategies to reduce the occurrence of skin cancer has become a highly desirable goal. Because UV radiation is known to cause excessive generations of reactive oxygen species (ROS) which in turn results in a situation known as oxidative stress, the approaches aimed at counteracting ROS production may be useful for the prevention of skin cancer. One approach to reduce its occurrence is through 'photochemoprotection', which we define as 'the use of agents capable of ameliorating the adverse effects of UVB on the skin'. Among many photochemoprotective agents, botanical antioxidants are showing promise. This review focuses on photochemopreventive effects of selected botanical antioxidants. We suggest that the use of botanical antioxidants in combination with the use of sunscreens and educational efforts to avoid excessive sun exposure may be an effective strategy for reducing incidence of skin cancer and other UV-mediated damages in humans.     

Photochemoprevention of skin cancer by botanical agents

Photochemoprevention has become an important armamentarium in the fight against ultraviolet radiation (UVR)-induced damage to the skin. Among many UVR-induced damages, skin cancer is of the greatest concern as its rates have been steadily increasing in recent years and the same trend is expected to continue in the future. Ultra-violet radiation increases oxidative stress in skin cells by causing excessive generation of reactive oxygen species (ROS), leading to cancer initiation and promotion. Antioxidants have the capability to quench these ROS and much recent work shows that some of these can inhibit many UVR-induced signal transduction pathways. Thus, identifying nontoxic strong antioxidants--capable of preventing UVR-induced skin cancer--has become an important area of research. The use of botanical antioxidants in skin care products is growing in popularity. A wide range of such agents has been shown to prevent skin cancer in animal model systems. New agents are constantly being investigated; however, only a few have been tested for their efficacy in humans. Animal model and cell culture studies have clarified that antioxidants act by several mechanisms at various stages of skin carcinogenesis. This review focuses on skin cancer photochemopreventive effects of selected botanical antioxidants.     

Photokarzinogenese

Ultraviolet (UV) radiation is the main carcinogen in the development of epithelial skin cancer. A variety of biological and molecular effects in the skin have been described. In order to avoid malignant transformation, various protective mechanisms have developed in the skin, whereby p53 plays a central role. UV signature mutations in p53, Ras and INK4a/ARF as well as UV-induced NFkappaB and cyclooxygenase 2 are principally involved in photocarcinogenesis. Chemoprevention has gained increasing importance for primary prevention. Numerous natural or synthetic substances can be antiinflammatory, antioxidative, proapoptotic or antiproliferative and suppress photocarcinogenesis. Extensive clinical data exist for the use of retinoids systemically or DNA repair enzymes topically. However, clinical trials are lacking, for example for green tea, which has been shown repeatedly to be chemoprotective in vitro and in mouse models after topical or oral application.     

Cutaneous photodamage,oxidative stress,and topical antioxidant protection

New methods to protect skin from photodamage from sun exposure are necessary if we are to conquer skin cancer and photoaging. Sunscreens are useful, but their protection is not ideal because of inadequate use, incomplete spectral protection, and toxicity. Skin naturally uses antioxidants (AOs) to protect itself from photodamage. This scientific review summarizes what is known about how photodamage occurs; why sunscreens--the current gold standard of photoprotection--are inadequate; and how topical AOs help protect against skin cancer and photoaging changes. This review is intended to be a reference source, including pertinent comprehensive reviews whenever available. Although not all AOs are included, an attempt has been made to select those AOs for which sufficient information is available to document their potential topical uses and benefits. Reviewed are the following physiologic and plant AOs: vitamin C, vitamin E, selenium, zinc, silymarin, soy isoflavones, and tea polyphenols. Their topical use may favorably supplement sunscreen protection and provide additional anticarcinogenic protection. (J Am Acad Dermatol 2003;48:1-19.) Learning objective: At the completion of this learning activity, participants should have an understanding of current information about how the sun damages skin to produce skin cancer and photoaging changes, how the skin naturally protects itself from the sun, the shortcomings of sunscreens, and the added advantages of topical AOs for photoprotection.     

Skin photodamage and lifetime photoprotection

Ultraviolet (UV) radiation is a very small part of the electromagnetic radiation spectrum, released and transported from the source in the form of photons. Disposal of these photons within the skin causes cutaneous photodamage, which leads to clinical, histologic, and biochemical changes. Aging is a complex process characterized by cellular attrition, decreased cellular reserve capacity, and compromised ability to perform normal cellular function. Intrinsic aging, which steadily develops with time, is linked to chronologic age; it is the result of a genetic program. Photoaging, on the other hand, develops as a consequence of UV radiation-induced degenerative changes in the skin. Intrinsic aging is a universal, inevitable process, whereas photoaging is neither universal nor inevitable and can be prevented. UV radiation can also suppress the immune system in both local and systemic way and lead to simultaneous and sequential biochemical events that ultimately cause photocarcinogenesis. Therefore, everyday use of products that protect against UV radiation is necessary to prevent acute and long-term photodamage (clinical and cellular changes) leading to photoaging, photoimmunosuppression, and photocarcinogenesis.     

Chemoprevention of skin cancer and photoaging

Skin cancer and photoaging are thought to be the result of ultraviolet radiation exposure. "Chemoprevention" refers to the prevention of photoaging and skin cancer through the use of pharmacologic agents that inhibit or reverse the process of photoaging or carcinogenesis. As both carcinogenesis and photoaging are multi-step processes, tumor development may be halted at several prospective points of intervention. A wealth of research aimed at chemoprevention is emerging. In this article, a variety of potential chemopreventive agents are discussed, including vitamins, diet, aspirin and non-steroidal anti-inflammatory drugs, and topical agents. Although further studies are warranted to identify and determine the safety and efficacy of new chemotherapeutic agents, it is expected that both systemic and topical agents may soon be available that effectively prevent photoaging and skin cancer development.     

A tan in a test tube - in vitro models for investigating ultraviolet radiation-induced damage in skin

Presently, global rates of skin cancers induced by ultraviolet radiation (UVR) exposure are on the rise. In view of this, current knowledge gaps in the biology of photocarcinogenesis and skin cancer progression urgently need to be addressed. One factor that has limited skin cancer research has been the need for a reproducible and physiologically-relevant model able to represent the complexity of human skin. This review outlines the main currently-used in vitro models of UVR-induced skin damage. This includes the use of conventional two-dimensional cell culture techniques and the major animal models that have been employed in photobiology and photocarcinogenesis research. Additionally, the progression towards the use of cultured skin explants and tissue-engineered skin constructs, and their utility as models of native skin's responses to UVR are described. The inherent advantages and disadvantages of these in vitro systems are also discussed.     

Tea polyphenols for the prevention of UVB‐induced skin cancer

Skin cancer is the most common type of cancer with increasing incidence rate and public health burden. Solar ultraviolet (UV) radiation causes an array of damaging cellular and molecular events that eventually lead to the development of skin cancer. Despite increased awareness about sun protection, the exposure rate remains high with less than 15% of men and 30% of women using sunscreen on a regular basis. Therefore, there is an imperative need for the development of novel preventive approaches. Skin cancer chemoprevention using phytochemicals either as dietary supplements or by topical applications has gained considerable attention due to their low toxicity, availability, and anticarcinogenic properties. Tea, the second most commonly consumed beverage in the world, is a rich source of promising phytochemicals known as polyphenols. In this review, we discuss the findings of various in vitro, in vivo and human studies signifying the chemopreventive effects of tea polyphenols against UVB‐induced skin cancer. This is accomplished by exploring the role of tea polyphenols in DNA repair, inflammation, oxidative stress, signaling pathways, and epigenetics. Finally, this review discusses a variety of innovative delivery methods that enhance the photochemopreventive effects of tea polyphenols against skin cancer.     

Cutaneous photoprotection from ultraviolet injury by green tea polyphenols

BACKGROUND: In animal models, extracts from green tea have been shown to be remarkably effective at reducing the severity of adverse human health effects of overexposure to ultraviolet (UV) radiation. Although sunscreens and other photoprotective measures have traditionally been used for this purpose, there is a need for additional measures and natural products are increasingly being explored for that purpose. OBJECTIVE: Our purpose was to evaluate the effect of polyphenols from green tea on parameters associated with acute UV injury. METHODS: Areas of skin of normal volunteers were treated with an extract of green tea or one of its constituents. Thirty minutes later, the treated sites were exposed to a 2 minimal erythema dose solar simulated radiation. UV-treated skin was examined clinically for UV-induced erythema, histologically for the presence of sunburn cells or Langerhans cell distributions, or biochemically for UV-induced DNA damage. RESULTS: Application of green tea extracts resulted in a dose-dependent inhibition of the erythema response evoked by UV radiation. The (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) polyphenolic fractions were most efficient at inhibiting erythema, whereas (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) had little effect. On histologic examination, skin treated with green tea extracts reduced the number of sunburn cells and protected epidermal Langerhans cells from UV damage. Green tea extracts also reduced the DNA damage that formed after UV radiation. CONCLUSION: Polyphenolic extracts of green tea are effective chemopreventive agents for many of the adverse effects of sunlight on human health and may thus serve as natural alternatives for photoprotection.     

Photoprotection in ethnic skin

Although cutaneous photodamage is partially mitigated by darker skin pigmentation, sun-induced aging, dyspigmentation, sunburns, and skin cancers are reported worldwide in all skin types and races. The severity of photodamage varies from individual to individual, and is predominantly based upon genetic differences altering the body's response or susceptibility to sun damage. In addition, non-Caucasian patients are less likely to perform skin self-examinations, attend dermatologic follow-ups, and seven times less likely to apply sunscreen than Caucasian patients. Therefore, the remainder of this article will discuss the categories of photoprotective agent [environmental, biologic, physical, and UV filters, i.e., sunscreens] as well as the topics of photoaging, dyspigmentation, photocarcinogenesis, and the controversy surrounding vitamin D deficiency from photoprotection in the context of ethnic skin.     

Chronic actinic damage of facial skin

Chronic actinic damage of the skin manifests itself as extrinsic skin aging (photoaging) and photocarcinogenesis. During the last decade, substantial progress has been made in understanding cellular and molecular mechanisms of photoaging. DNA photodamage and ultraviolet-generated reactive oxygen species are the initial events that lead to most of the typical histologic and clinical manifestations of chronic photodamage of the skin. Chronic actinic damage affects all layers of the skin. Keratinocytes, melanocytes, fibroblasts, and endothelial cells are altered by ultraviolet radiation and can result in numerous changes in human skin, particularly the skin of fair-skinned individuals. These changes include actinic keratosis, thickening and wrinkling, elastosis, telengiectasia, solar comedones, diffuse or mottled hyperpigmentation, and skin cancers. There are many options in the treatment of changes caused by chronic actinic damage. The most effective measure of prevention of the photoaging and photocarcinogenesis is sun protection.     

Antioxidants and the skin: Understanding formulation and efficacy

Antioxidants are molecules capable of inhibiting the oxidation of other molecules. Although oxidation reactions are essential for life, they can also be damaging. All living organisms maintain complex systems of multiple types of antioxidants to protect their cells from oxidative damage. Antioxidants can also act as pro-oxidants, under certain circumstances. The efficacy and benefit of an antioxidant is, therefore, very much dependent on the delivery of the antioxidant to the organism. Topically applied antioxidants constitute an important group of pharmacologically active agents capable of preventing the occurrence and reducing the severity of UV-induced skin damage and skin aging. Antioxidants protect skin cells against the damaging effects of reactive oxygen species (ROS), such as singlet oxygen, superoxide, peroxyl radicals, hydroxyl radicals, and peroxynitrite. ROS induced oxidative stress in the skin has been linked to cancer, aging, inflammation, and photodamage. This review focuses on antioxidants used in the cosmetic industry for protection of skin, formulation methods used to enhance their efficacy, and methods used to test the efficacy of antioxidants in topical formulations.