Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewPhotochemoprevention of ultraviolet B signaling and photocarcinogenesis
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
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