Abstract 4286: Oral caffeine during voluntary exercise markedly inhibits skin carcinogenesis and decreases cytokines associated with inflammation in UVB-treated mice

Abstract

Abstract In previous studies, we found that treatment of female SKH-1 mice with either oral administration of caffeine or voluntary running wheel exercise (RW) inhibited the formation of UVB-induced skin tumors. In the present study, we determined whether RW in combination with oral caffeine has a synergistic inhibitory effect on UVB-induced skin carcinogenesis. UVB-pretreated female high-risk SKH-1 mice (7-8 weeks of age, total 160 mice) have no tumors but they develop tumors in the absence of further UVB irradiation over the next several months. These high-risk mice (40 mice per group) were then treated with water (control), caffeine (0.1 mg/ml in drinking fluid), RW or caffeine together with RW for 14 weeks. Although there were no differences in body weight between the four groups during the course of the study, treatment with caffeine increased running wheel activity by 40% when compared with RW alone. Treatment of the mice with caffeine, RW or caffeine together with RW decreased skin tumors per mouse by 27, 35 and 62%, respectively, and the tumor volume per mouse was decreased by 61, 70 and 85%, respectively. In mechanistic studies, female SKH-1 mice were treated with water (control), caffeine (0.1 mg/ml), RW, or a combination of caffeine plus RW for 2 weeks. All mice were then exposed to a single dose of UVB (30 mJ/cm2) and sacrificed before (control) and at 0.1, 0.5, 1, 2, 4, 6, 10, 16, 24, and 48 h post UVB. The results showed that mice treated with oral caffeine for 2 weeks increased RW activity by 22% when compared with the mice treated with RW alone. Treatment of mice orally with caffeine, RW, or a combination of caffeine and RW for 2 weeks (a) decreased the weight of the parametrial fat pads by 30, 56 and 63%, respectively, (b) stimulated the formation of UVB-induced apoptotic sunburn cells in the epidermis by 21, 124 and 298% at 6 hours post-UVB, and stimulated the formation of UVB-induced caspase 3 (active form) positive cells in the epidermis by 30, 164 and 333%, respectively at 6 hours post-UVB. Combination treatment of the mice had a small but significant inhibitory effect on cell proliferation as measured by bromodeoxyuridine incorporation into DNA in the epidermis. Antibody array with 40 cytokines associated with inflammation revealed that oral caffeine together with RW administered to mice fed a high fat diet rich in omega-6 fatty acids for 2 weeks significantly decreased the UVB-induced increases in the levels of LIX, sTNF R1 and MIP-1α as well as several other cytokines associated with inflammation. Our results indicate that voluntary exercise in combination with oral caffeine exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis in UVB-pretreated high-risk mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4286. doi:1538-7445.AM2012-4286