Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice

Abstract

SKH-1 hairless mice were irradiated with ultraviolet B (UVB) twice weekly for 20 weeks. These tumor-free mice, which had a high risk of developing skin tumors during the next several months, were then treated topically with caffeine (6.2 mol) or (؊)-epigallocatechin gallate (EGCG; 6.5 mol) once a day 5 days a week for 18 weeks in the absence of further treatment with UVB. Topical applications of caffeine to these mice decreased the number of nonmalignant and malignant skin tumors per mouse by 44% and 72%, respectively. Topical applications of EGCG decreased the number of nonmalignant and malignant tumors per mouse by 55% and 66%, respectively. Immunohistochemical analysis showed that topical applications of caffeine or EGCG increased apoptosis as measured by the number of caspase 3-positive cells in nonmalignant skin tumors by 87% or 72%, respectively, and in squamous cell carcinomas by 92% or 56%, respectively, but there was no effect on apoptosis in nontumor areas of the epidermis. Topical applications of caffeine or EGCG had a small inhibitory effect on proliferation in nonmalignant tumors as measured by BrdUrd labeling (16 -22%), and there was also a similar, but nonsignificant, inhibitory effect on proliferation in malignant tumors. The results suggest a need for further studies to determine whether topical applications of caffeine or EGCG can inhibit sunlight-induced skin cancer in humans.tea constituents ͉ programmed cell death ͉ caspase 3 S kin cancer is a major cancer in the United States, and its incidence is expected to increase substantially because of increased recreational exposure to sunlight and depletion of the ozone layer (1, 2). The identification and use of protective agents should have an important impact on the formation of these cancers. Although the use of sunscreens is an approach that has decreased the risk of skin cancers (3, 4), there is also a need to identify additional approaches for skin cancer prevention in individuals previously exposed to high-dose levels of sunlight (high-risk individuals). Treatment of SKH-1 hairless mice with ultraviolet B (UVB) (30 mJ͞cm 2 ) twice a week for 20 weeks resulted in mice without tumors but with epidermal hyperplasia and a high risk of developing skin tumors during the next several months in the absence of further UVB treatment (initiated high-risk mice) (5). This animal model resembles humans who are heavily exposed to sunlight early in life and then have reduced exposure later in life. We have used UVB-pretreated high-risk mice for evaluating the effects of potential chemopreventive agents on skin tumor formation in the absence of further exposure to UVB. Oral administration of green tea, black tea, or caffeine to UVBpretreated high-risk mice inhibited tumorigenesis, but the decaffeinated teas had little or no activity, and reconstitution of the decaffeinated teas with caffeine restored biological activity (5). These observations indicate that caffeine is a major cancer chemopreventive constituent in tea. Potential antitumor mechanisms include...

Inhibition of carcinogenesis by tea constituents

“…When tea polyphenols are administered orally, their low bioavailability in the skin may limit the inhibitory effect; the contribution of caffeine present in tea to inhibiting carcinogenesis could become more important. Topical application of EGCG and caffeine to the skin was shown to decrease, by a similar extent, the incidence, multiplicity, and size of tumors induced by UVB treatment in SKH-1 mice [38,39].…”

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

“…52 Accordingly, pre-exposure of SKH-1 hairless mice to caffeine resulted in an enhanced rate of UVB-induced apoptosis in the epidermis 53 and protected the animals against photocarcinogenesis. 54 In addition, epidemiological data imply that daily caffeinated coffee consumption decreases the incidence and prevalence of NMSC in Caucasians, 55,56 indicating that CHK1 inhibition is indeed effective in terms of cancer chemoprevention in humans. As overexpression of CHK1 attenuated the enhanced apoptosis rate of UVB-exposed NCTC-shAHR KC, it is highly likely that the loss of checkpoint control drives damaged KC into the suicide program ( Figure 5).…”

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

“…EGCG exerts an inhibitory effect in many cancers, such as prostate cancer [20,21] and liver cancer [22] . Previous studies have shown that EGCG decreased the expression of COX-2 [23] and mPGES [15] .…”