Dietary polyphenols have gained considerable attention for the prevention of UV-induced skin photodamage including the risk of skin cancer. Polyphenols possessing anti-inflammatory, immunomodulatory, DNA repair capability, and can correct undesired cellular functions are among the most promising group of compounds that can be exploited as ideal chemopreventive agents. Chemoprevention offers a practical approach to delineate substances, either components of food or pharmaceuticals, which can prevent, delay or completely halt the process of photocarcinogenesis. For a variety of reasons, among many chemopreventive agents known, there is greater emphasis on substances present in diet and beverages commonly consumed by humans. In this respect, chemoprevention offers a realistic strategy for controlling the risk of skin cancers because agents can be targeted for intervention at the initiation, promotion, or progression stage of the multistage photocarcinogenesis. An ideal chemopreventive agent for human use should have: (i) little or no toxicity, (ii) anti-mutagenic and anti-carcinogenic activities, (iii) striking inhibitory effects on diverse cellular events associated with multistage photocarcinogenesis, (iv) high efficacy in multiple sites, (v) capability of oral consumption, (vi) a known mechanism of action, (vii) affordable low cost, and (viii) human acceptance [28
]. Furthermore, the individuals can modify their dietary habits and lifestyle in combination with a careful use of skin care products to prevent UVB-mediated skin damage. In this Mini Review Article, we have summarized and discussed the molecular targets or mechanism(s) of action of some of the selected polyphenols (such as green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, silymarin, resveratrol, genistein and delphinidin) against UV radiation-induced inflammation, immunosppression, prevention of DNA damage, DNA repair, modulation of cell signaling pathways critically involved in different stages of photocarcinogenesis ().
A summary of molecular mechanism(s)/cellular targets of some selected polyphenols in skin photoprotection.
It is well established that exposure of the skin to UV radiation contributes to the development of skin cancers. Epidemiological, clinical and pre-clinical studies have implicated that solar UV radiation is the major etiological factor in the development of cutaneous malignancy [4
], including the nonmelanoma skin cancers which represent the most common malignant neoplasms in humans [31
]. Various animal models have been employed to examine the anti-photocarcinogenic effects of plant polyphenols. The plant polyphenols possess anti-inflammatory, immunomodulatory, anti-oxidant properties and DNA repair activities, and that can be exploited for the prevention of variety of skin disorders caused by excessive exposure to solar UV light. Recent advances in our understanding at the cellular and molecular levels of photocarcinogenesis have led to the development of promising strategies for the skin photoprotection including photocarcinogenesis. Studies have shown the photoprotective potential of several plant polyphenols, such as green tea polyphenols (GTPs), silymarin, retinoids, grape seed proanthocyanidins (GSPs), and delphinidin, etc. against UV radiation-induced adverse effects [33
]. Here, we will summarize and discuss the recent developments in the area of anti-photocarcinogenic potential of some selected polyphenols which were studied extensively.
Following standard photocarcinogenesis protocols, topical application or oral administration of green tea polyphenols (GTPs) in drinking water of mice resulted in lower tumor burden in terms of tumor incidence and tumor multiplicity in these animals compared to non-GTPs-fed control group of mice [36
]. Oral feeding of green tea or injection of GTPs fraction or EGCG to mice was found to inhibit the growth and/or caused the regression of established experimentally-induced nonmalignant skin papilloma in mice [41
]. Histopathological examination of each tumor showed that oral administration of green tea had a marked inhibitory effect on the formation of UVB-induced keratoacanthomas and carcinomas [42
]. Meeran et al.
] employed interleukin-12 knockout (IL-12 KO) mice to elucidate whether the induction of IL-12 by EGCG is associated for its protective effect against photocarcinogenesis. It was tested because IL-12 has been shown to have anti-tumor activity and DNA repair ability in mice. Topical application of EGCG to wild-type mice resulted in a significant reduction in UVB-induced skin tumorigenesis in terms of tumor incidence and tumor multiplicity compared with non–EGCG-treated wild-type mice. However, topical application of EGCG to IL-12 KO mice did not protect photocarcinogenesis. These observations suggest that chemopreventive effect of green tea against photocarcinogenesis requires IL-12 or mediated through IL-12-based mechanism.
Pomegranate fruit extract (PFE) is a rich source of anthocyanins, ellagitannins and hydrolyzable tannins and possesses strong antioxidant activity [44
]. Oral feeding of PFE to SKH-1 hairless mice in a UVB initiation-promotion protocol resulted in reduced tumor incidence, delay in the latency period of tumor appearance, and lower tumor body burden compared to that of non-PFE-treated and UVB-irradiated control animals [45
]. Dietary grape seed proanthocyanidins (GSPs) supplemented with AIN76 control diet significantly lowered the tumor multiplicity and growth or size of the tumor in SKH-1 hairless mouse model in UVB-induced complete (both initiation + promotion) photocarcinogenesis protocol. Dietary GSPs also resulted in prevention and delay of malignant transformation of UVB-induced papillomas to carcinomas in terms of carcinoma incidence, carcinoma multiplicity and carcinoma growth [46
]. Aziz et al.
] have shown that topical application of resveratrol both pre- and post-UVB irradiation of SKH-1 hairless mice resulted in a significant inhibition in tumor incidence, and delay in the onset of tumorigenesis. Post-application of resveratrol was found to impart almost equal protection compared to pre-application, suggesting that resveratrol-mediated chemopreventive effects may not be due to sunscreen effects. Treatment of p53+/−
/SKH-1 mice with resveratrol by oral gavage reduced the average number of skin tumors and the average tumor volume compared with non-resveratrol treated and UV-exposed control group of mice. In addition, the number of SCCs in resveratrol-treated mice was less than non-resveratrol treated control mice [48
Topical treatment of SKH-1 hairless mouse skin with silymarin, a flavonoid from milk thistle (Silybum marianum
), significantly reduced UVB-induced tumor incidence, tumor multiplicity, and average tumor volume per mouse compared to non-silymarin treated UVB-exposed mice. Silymarin was effective in protecting the skin against all the stages of photocarcinogenesis, such as UV-induced tumor initiation, tumor promotion, and complete carcinogenesis (initiation + promotion) protocols [49
]. Topical treatment of mouse skin with silibinin, a major component of silymarin, before or immediately after UVB irradiation or given in diet afforded protection against photocarcinogenesis in terms of delay in tumor appearance, tumor multiplicity and tumor volume [50
]. Multiple in vitro
and in vivo
studies suggest anti-photocarcinogenic potential of plant polyphenols, we will briefly summarize and discuss the molecular mechanisms responsible for anti-photocarcinogenic effect of these selected polyphenols.