Abstract 1815: Stimulation of apoptosis by caffeine or exercise is associated with an increase in thymine dimer formation in the epidermis of UVB-treated SKH-1 mice

In early studies, we found that oral administration of caffeine or voluntary running wheel exercise (RW) for 1 or 2 weeks prior to UVB irradiation enhanced UVB-induced apoptosis in the epidermis of SKH-1 hairless mice. In additional studies, we found that oral administration of caffeine or RW during the course of irradiation with UVB inhibited UVB-induced skin carcinogenesis. In the present study, we explored the possible mechanism for the effect of caffeine administration or RW to stimulate UVB-induced apoptosis in the epidermis of SKH-1 mice. Female SKH-1 mice (5 mice per time point) were treated with: (1) oral water (control), (2) oral caffeine (0.1 mg/ml in the drinking water) (3) RW, or (4) 0.1 mg/ml oral caffeine plus RW for 2 weeks. The pretreated mice were then exposed to a single irradiation with UVB (30 mJ/cm2) and sacrificed at 0 (no UVB treatment), or at 5 min, 0.5h, 1h, 2h, 4h, 6h, 10h, 16h, 24h and 48h after UVB. The results showed that oral caffeine, RW, or caffeine plus RW for 2 weeks stimulated UVB-induced caspase 3 positive cells by 30%, 164% or 333%, respectively, at 6 hr after UVB (peak timepoint for UVB-induced apoptosis). These treatments had little inhibitory effect on cell proliferation. Unexpectedly, all of these treatments enhanced UVB-induced thymine dimer formation as measured by immunohistochemistry. Oral caffeine, RW, or the combination of caffeine and RW increased UVB-induced thymine dimer positive cells by 52%, 56% or 75%, respectively at 0.5 hr after UVB (peak for UVB-induced thymine dimer formation), when compared to the water control group. Thymine dimer positive cells were gone by 48 h post-UVB. The effect of caffeine and RW to increase the number of thymine dimer positive cells preceded the increase in apoptosis in the epidermis of UVB irradiated mice. Slot-blot analysis of isolated epidermal DNA from the mice treated with oral caffeine, RW or their combination for 2 weeks for thymine dimers confirmed the immunohistochemistry data. In a separate experiment, mice treated with instant coffee (10 mg coffee solids/ml) or caffeine (0.4 mg/ml) in the drinking fluid for one week prior to UVB irradiation showed enhanced UVB-induced increase in thymine dimer positive cells by 75-80% at 15-30 min post-UVB compared with water control mice irradiated with UVB. The coffee-induced increase in thymine dimer positive cells was followed by an increase in apoptosis (about 2-fold) at 6-10 hr post-UVB. Our results indicate that RW, oral administration of caffeine or coffee increase UVB-induced thymine dimers in DNA followed by an increase in apoptosis in the epidermis. We hypothesize that caffeine- or voluntary running wheel exercise-induced increase in thymine dimers may play a role in the ability of caffeine administration and RW to increase UVB-induced apoptosis and to inhibit UVB-induced carcinogenesis (Supported by NIH Grants RO1 CA128997 and RO1CA114442). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1815. doi:10.1158/1538-7445.AM2011-1815