ReviewStimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice
Section snippets
Effects on UVB-induced complete carcinogenesis
Our interest in caffeine developed after finding that although oral administration of green and black tea inhibited UVB-induced complete carcinogenesis in SKH-1 mice, the decaffeinated teas were inactive, and high dose levels of the decaffeinated teas actually increased UVB-induced carcinogenesis (Huang et al., 1997). Adding back caffeine to the decaffeinated teas restored their inhibitory effects on UVB-induced carcinogenesis, and administration of caffeine alone had a strong inhibitory effect
Plasma and tissue levels of caffeine and its metabolites in SKH-1 mice treated orally with caffeine for 2 weeks
Since oral administration of caffeine (0.36–0.44 mg/ml in drinking water) inhibited UVB-induced carcinogenesis (Huang et al., 1997, Lou et al., 1999), we determined the concentrations of caffeine and its metabolites in the plasma, epidermis and dermis of SKH-1 mice treated with caffeine (0.44 mg/ml in the drinking water) for 2 weeks, and the results of this study are shown in Table 3. The levels of caffeine and its metabolites were measured by HPLC as described by Guru and Icen (2004) and
Stimulatory effect of oral administration of green tea, coffee or caffeine on UVB-induced increase in apoptosis
SKH-1 mice were treated with orally administered green tea (6 mg tea solids/ml), 1% instant coffee (10 mg coffee solids/ml) or caffeine (0.4 mg/ml) as their sole source of drinking fluid for 2 weeks prior to a single irradiation with UVB. These treatments stimulated UVB-induced apoptosis by 204%, 109% and 191%, respectively, at 10 h post UVB, but the treatments with tea, coffee or caffeine had no effect on apoptosis in the absence of UVB treatment (Fig. 1).
Effects of oral administration of caffeine on tissue fat
During our studies on the effects of tea and caffeine on carcinogenesis, we found that administration of caffeine or the regular teas decreased the size of the parametrial fat pad and the thickness of the dermal fat layer, but the decaffeinated teas did not have this effect (Lu et al., 2001). In these studies, there was a relationship between the thickness of the dermal fat layer and the number of tumors per mouse (Lu et al., 2001). Animals with a thinner dermal fat layer had fewer tumors. We
Inhibitory effect of topical applications of caffeine on carcinogenesis in high risk mice
Topical applications of caffeine to UVB-pretreated “high risk mice” in the absence of further treatment with UVB inhibited skin tumorigenesis (Table 4) (Lu et al., 2002a). In this experiment, mice were irradiated with UVB (30 mJ/cm2) twice a week for 20 weeks and UVB treatment was stopped. About 3 weeks later, these tumor-free high risk mice (30 mice/group) were treated topically with 100 μl of acetone or with caffeine (6.2 μmol) in 100 μl of acetone once a day 5 days a week for 18 weeks and
Stimulatory effect of topical applications of caffeine on apoptosis in tumors in high risk mice
The results of immunohistochemical staining of the tumors described in Table 4 indicated that topical applications of caffeine to high risk mice enhanced apoptosis in the tumors but not in areas away from the tumors (Table 5) (Lu et al., 2002a). These results suggest that the inhibitory effect of caffeine administration on tumorigenesis in high risk mice may be caused in part by enhanced apoptosis in tumors during their formation.
Studies with topically applied caffeine sodium benzoate
In an early study, we found that topical application of caffeine immediately after UVB enhanced apoptosis at 6–10 h post-UVB (Lu et al., 2002b). In recent studies, we found that topical application of caffeine sodium benzoate immediately after UVB exposure was about fivefold more potent than caffeine at enhancing UVB-induced apoptosis, and caffeine citrate was also more active than caffeine (Lu et al., in press). It is not known if the enhanced activity of the caffeine complexes was because of
Caffeine administration has different effects in different animal models
Administration of caffeine orally or by injection inhibits carcinogenesis in several animal models, but carcinogenesis is enhanced in some animal models (reviewed in Conney et al., 2002). For instance, oral administration of caffeine to rats inhibits 2-amino-1-methyl-6-phenylimazo[4,5-b] pyridine (PhIP)-induced breast cancer (Hagiwara et al., 1999) and 2-acetylaminofluorene-induced liver cancer (Hosaka et al., 2001), but PhIP-induced colon cancer and DMBA-induced breast cancer are enhanced (
Concluding remarks
The results of our studies indicate that oral or topical administration of caffeine inhibits UVB-induced carcinogenesis in SKH-1 mice at least in part by enhancing UVB-induced apoptosis and by enhancing apoptosis in UVB-induced tumors in tumor-bearing mice. Caffeine sodium benzoate is more active than caffeine in stimulating UVB-induced apoptosis. Mechanistic studies indicate that caffeine administration enhances UVB-induced apoptosis by enhancing UVB-induced increases in wild-type p53 and by
Acknowledgments
Supported in part by NIH grants: R35 CA49756, R01 CA80759, and P01 CA88961.
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