Review
Photochemoprevention of ultraviolet B signaling and photocarcinogenesis

https://doi.org/10.1016/j.mrfmmm.2004.07.019Get rights and content

Abstract

Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.

Introduction

In the United States, alone 1.2 million new cases of skin cancer are identified each year, and this accounts for 40% of all new cancer cases that are diagnosed [1], [2]. Solar ultraviolet (UV) B radiation has been implicated as the main cause for skin cancer. UV radiation in sunlight is divided into three regions depending on wavelength, short-wave UVC (200–280 nm), mid-wave UVB (280–320 nm) and long-wave UVA (320–400 nm). UVC has the highest energy and, hence, is the most biologically damaging region of UV radiation. However, UVC in solar radiation is filtered out by ozone layer of the Earth's atmosphere, and therefore, its role in human pathogenesis is minimal. Both UVB, and to a lesser extent, UVA radiation are responsible as a causative factor for various skin disorders including skin cancer [3], [4], [5], [6]. Because greater than 90% of the solar radiation at the earth's surface is UVA (320–400 nm), in recent years, the role of UVA in skin carcinogenesis has begun to be appreciated. It has become clear that UVA accounts for at least 10% of the carcinogenic dose of the sunlight.

The non-melanoma skin cancers (NMSCs) comprising of basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), are the most frequently diagnosed cutaneous malignancies and account for approximately 80 and 16% of all skin cancers, respectively, whereas malignant melanomas account for only 4% of all skin cancers. Both BCCs and SCCs are derived from the basal layer of the epidermis of the skin. SCCs are invasive, and more than 10% of these cancers metastasise. On the other hand, BCCs do not metastasize but can be locally invasive and destructive [7], [8], [9]. In the year 2004, 55,100 newly diagnosed cases of melanoma, resulting in ∼7910 deaths are expected to occur, while 2340 deaths are expected to occur from non-epithelial skin cancers [10]. Less common but more aggressive forms of skin cancer include Kaposi's sarcoma and cutaneous T-cell lymphoma.

Considerable body of evidence suggests that SCCs and BCCs are the most frequently diagnosed cutaneous malignancies and occur primarily on sun-exposed areas of the body and have been strongly associated with chronic sun exposure [3], [4], [5], [9], [11]. For primary prevention of photodamage and cutaneous disease, education about the harmful effects of UV radiation present in the sunlight, the need to avoid its excessive exposure by wearing protective clothing, and the use of sunscreen has been emphasized, but for many reasons, these primary prevention approaches have had limited success [9], [11]. Therefore, additional efforts are needed to prevent skin cancers that result as a consequence of UVB exposure. Because skin cancer is a significant problem associated with mortality and morbidity concerted efforts are needed to develop novel strategies for the prevention of UV responses. One such approach to ameliorate the occurrence of skin cancer is through chemoprevention, which by definition is a means of cancer control in which the occurrence of the disease can be entirely prevented, slowed or reversed by topical or oral administration of naturally occurring or synthetic compound or their mixtures [9], [11], [12]. These chemopreventive compounds are known to be anti-mutagenic, anti-carcinogenic and non-toxic, and have the ability to exert striking inhibitory effects on diverse cellular events associated with multistage carcinogenesis. For chemoprevention of photodamages including photocarcinogenesis, we have coined the term ‘photochemoprotection’ [11], [13]. These photochemopreventive agents for human use should have the ability to ameliorate the adverse biological effects of UV radiation.

The skin, situated at the interface between the body and its environment, directly suffers from the deleterious effects of UV radiation. This UV radiation jeopardizes the integrity of the skin that is critical for cellular homeostasis. UV radiation results in an increased generation of reactive oxygen species (ROS) that overwhelms the antioxidant defense mechanisms of the target system. This condition of prooxidant/antioxidant disequilibrium is defined as ‘oxidative stress’. The epidermis is composed mainly of keratinocytes, which are rich in ROS detoxifying enzymes, such as superoxide dismutase, catalase, thioredoxin reductase, and glutathione peroxidase, and in low-molecular-mass antioxidant molecules, such as tocopherol, glutathione and ascorbic acid, and thus provides some natural protection against ROS [14], [15], [16]. Skin spontaneously responds to increased ROS levels; however, this response may not be sufficient to prevent the progression of skin cancer. Studies have shown that UV radiation to the skin results in the formation of ROS that interact with proteins, lipids and DNA [17], [18], [19]. UV radiation to mammalian skin is known to alter cellular function via DNA damage [20], [21], [22], generation of ROS [23], [24], [25], and the resultant alterations in a variety of signaling events [9], [23], [26], [27], [28]. The cause of these events is contingent upon the UV dose, time of exposure and the wavelength. Studies have demonstrated that oxidative stress elicited by UV irradiation activates redox-sensitive transcription factors, including nuclear factor-kappa B (NF-κB) [27], [28], [29], and members of the activator protein-1 (AP-1) complex, such as c-Fos and c-Jun [30], [31].

The development of skin cancer is a complex multistage phenomenon involving three-distinct stages initiation–promotion–progression-mediated via various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that changes the response of initiated basal stem cells of the epidermis. Tumor promotion is the process that involves clonal expansion of initiated cells giving rise to pre-malignant and malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. To name a few, these processes entail: (i) stimulation of DNA synthesis, DNA damage, and proliferation, (ii) inflammation, (iii) immunosuppression, (iv) epidermal hyperplasia, (v) cell cycle dysregulation, (vi) depletion of antioxidant defenses, (vii) impairment of signal transduction pathways, (viii) induction of cyclooxygenase, (ix) increase in prostaglandin synthesis, and (x) induction of ornithine decarboxylase [9], [11], [32].

In this article, we have summarized the available information based on laboratory studies on the effects of UV radiation on cellular signaling (Fig. 1, Fig. 2). We have further dealt in detail on the use of photochemopreventive agents and how they could be exploited to target signaling molecules for photochemoprevention of UVB-mediated adverse effects.

Section snippets

Mechanism of photochemoprevention

In recent years, photochemoprevention has matured into an accepted modality for controlling skin cancer. Although photochemoprevention can be achieved by intervention at initiation or promotion phases of skin tumorigenicity for a variety of reasons; for example, availability of sunscreens to prevent penetration of UV radiation, anti-tumor promoting agents appear to have greater likelihood for success in humans. Thus, it is important to identify mechanism-based effective novel

UVB-mediated inflammation and immunosuppression

Inflammation that includes the release of growth factors, proinflammatory cytokines, infiltration of inflammatory cells, and ROS production, plays an important role in skin cancer development. Chronic UVB-mediated inflammation causes the induction of the Cyclooxygenase-2 (COX-2) enzyme in the skin, resulting in increased prostaglandin levels, inflammatory cell infiltration and activation, and further oxidant production [40], [41]. Cyclobutane pyrimidine dimers are primarily produced in

Conclusions and future directions

Over the years, changes in lifestyle have led to a significant increase in the amount of UVB radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. For primary prevention of photodamage and cutaneous disease, education about the harmful effects of UV radiation present in the sunlight, the need to avoid its excessive exposure by wearing protective clothing, and the use of sunscreen has been emphasized, but for many reasons, these primary

References (187)

  • S.K. Katiyar et al.

    Inhibition of UVB-induced oxidative stress-mediated phosphorylation of mitogen-activated protein kinase signaling pathways in cultured human epidermal keratinocytes by green tea polyphenol (−)-epigallocatechin-3-gallate

    Toxicol. Appl. Pharmacol.

    (2001)
  • K. Isoherranen et al.

    Differential regulation of the AP-1 family members by UV irradiation in vitro and in vivo

    Cell Signal.

    (1998)
  • Y. Matsumura et al.

    Toxic effects of ultraviolet radiation on the skin

    Toxicol. Appl. Pharmacol.

    (2004)
  • F.P. Noonan et al.

    Immunosuppression of ultraviolet B radiation: initiation by urocanic acid

    Immunol. Today

    (1992)
  • L.H. Kligman et al.

    Sunscreens prevent ultraviolet photocarcinogenesis

    J. Am. Acad. Dermatol.

    (1980)
  • F. Marks et al.

    Cancer chemoprevention through interruption of multistage carcinogenesis: the lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer

    Eur. J. Cancer

    (2000)
  • M. Athar et al.

    Ultraviolet B (UVB)-induced cox-2 expression in murine skin: an immunohistochemical study

    Biochem. Biophys. Res. Commun.

    (2001)
  • Y. Sontag et al.

    Cells with UV-specific DNA damage are present in murine lymph nodes after in vivo UV irradiation

    J. Invest. Dermatol.

    (1995)
  • L. Meunier et al.

    In human dermis, ultraviolet radiation induces expansion of a CD36+CD11b+ CD1 macrophage subset by infiltration and proliferation: CD1+ Langerhans-like antigen-presenting cells are concomitantly depleted

    J. Invest. Dermatol.

    (1995)
  • C.A. Elmets et al.

    Cutaneous photoprotection from ultraviolet injury by green tea polyphenols

    J. Am. Acad. Dermatol.

    (2001)
  • M. Athar et al.

    Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity in the skin of SKH-1 hairless mice

    Toxicol. Appl. Pharmacol.

    (2004)
  • C. Hammerberg et al.

    Temporal correlation between UV radiation locally-inducible tolerance and the sequential appearance of dermal, then epidermal, class II MHC+ CD11b+ monocytic/macrophagic cells

    J. Invest. Dermatol.

    (1996)
  • B.J. Nickoloff et al.

    Life and death signaling pathways contributing to skin cancer

    J. Investig. Dermatol. Symp. Proc.

    (2002)
  • W.S. el-Deiry et al.

    WAF1, a potential mediator of p53 tumor suppression

    Cell

    (1993)
  • A.J. Levine

    p53, the cellular gatekeeper for growth and division

    Cell

    (1997)
  • E. Healy et al.

    Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants

    J. Invest. Dermatol.

    (1994)
  • S.-Y. Shieh et al.

    DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2

    Cell

    (1997)
  • M. Piepkorn

    The expression of p16 (INK4a), the product of a tumor suppressor gene for melanoma, is upregulated in human melanocytes by UVB irradiation

    J. Am. Acad. Dermatol.

    (2000)
  • N.U. Ahmed et al.

    Induced expression of p16 and p21 proteins in UVB-irradiated human epidermis and cultured keratinocytes

    J. Dermatol. Sci.

    (1999)
  • M. Serrano et al.

    Role of the INK4a locus in tumor suppression and cell mortality

    Cell

    (1996)
  • J.A. Bush et al.

    Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53

    Exp. Cell Res.

    (2001)
  • S.H. Jee et al.

    Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells

    J. Invest. Dermatol.

    (1998)
  • S.L. Parker et al.

    Cancer statistics, 1997

    CA Cancer J. Clin.

    (1997)
  • F.R. De Gruijil et al.

    Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice

    Cancer Res.

    (1993)
  • A.R. Young

    Cumulative effects of ultraviolet radiation on the skin: cancer and photoaging

    Semin. Dermatol.

    (1990)
  • G.T. Bowden

    Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signaling

    Nat. Rev. Cancer

    (2004)
  • A. Jemal et al.

    Cancer statistics, 2004

    CA Cancer J. Clin.

    (2004)
  • F. Afaq et al.

    Botanical antioxidants for chemoprevention of photocarcinogenesis

    Front. Biosci.

    (2002)
  • N. Ahmad et al.

    Cutaneous photochemoprevention by green tea: a brief review

    Skin. Pharmacol. Appl. Skin Physiol.

    (2001)
  • S. F’guyer et al.

    Photochemoprevention of skin cancer by botanical agents

    Photodermatol. Photoimmunol. Photomed.

    (2003)
  • G. Li et al.

    Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice

    Am. J. Pathol.

    (1996)
  • M.J. Peak et al.

    Photosensitized inactivation of DNA by monochromatic 334-nm radiation in the presence of 2-thiouracil: genetic activity and backbone breaks

    Photochem. Photobiol.

    (1988)
  • H.N. Ananthaswamy et al.

    Molecular alterations in human skin tumors

    Prog. Clin. Biol. Res.

    (1992)
  • S.K. Katiyar et al.

    Green tea polyphenol treatment to human skin prevents formation of ultraviolet light B-induced pyrimidine dimers in DNA

    Clin. Cancer Res.

    (2000)
  • S.K. Katiyar et al.

    Green tea polyphenol (−)-epigallocatechin-3-gallate treatment of human skin inhibits ultraviolet radiation-induced oxidative stress

    Carcinogenesis

    (2001)
  • C.S. Sander et al.

    Role of oxidative stress and the antioxidant network in cutaneous carcinogenesis

    Int. J. Dermatol.

    (2004)
  • Y.J. Surh

    Cancer chemoprevention with dietary phytochemicals

    Nat. Rev. Cancer

    (2003)
  • F. Afaq et al.

    Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor-kappa B by green tea polyphenol in SKH-1 hairless mice

    Oncogene

    (2003)
  • F. Afaq et al.

    Inhibition of ultraviolet B-mediated activation of nuclear factor-kappaB in normal human epidermal keratinocytes by green tea constituent (−)-epigallocatechin-3-gallate

    Oncogene

    (2003)
  • M. Djavaheri-Mergny et al.

    UV-A-induced decrease in nuclear factor-kappaB activity in human keratinocytes

    Biochem. J.

    (1999)
  • Cited by (0)

    View full text