Caffeine sodium benzoate is a potent inhibitor of UVB-induced skin carcinogenesis in SKH-1 hairless mice

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Topical applications of caffeine sodium benzoate (CSB, 6.2 μmole) in acetone to the dorsal skin of female SKH-1 hairless mice immediately after UVB irradiation and 0.5 and 2 hr later stimulated UVB-induced formation of apoptotic sunburn cells by 434% at 6 hr post-UVB. The potency of the apoptosis-enhancing effect of various caffeine complexes was CSB > caffeine triiodide > caffeine citrate > caffeine > caffeine nicotinate. In a separate experiment, a single topical application of 1, 2, 4 or 8% CSB in dermabase (an oil in water emulsion; dermatological cream) or an equimolar amount of caffeine (0.6, 1.2, 2.4, or 4.8%) had a strong stimulatory effect on UVB-induced apoptosis, and CSB was 2- to 3- times more active than caffeine. Topical application of CSB or caffeine had no effect on apoptosis in non-UVB-treated mouse epidermis. In tumorigenesis studies, we found that topical application of 2% or 6% CSB in dermabase once a day five days a week markedly inhibited the formation of skin tumors in mice previously treated chronically with UVB (tumor-free high risk mice). Application of CSB to high risk mice not only inhibited the formation of skin tumors, but tumor size was also substantially decreased. Histological examination of tumors in high risk mice receiving topical application of 3.6% caffeine in dermabase or an equimolar concentration of CSB (6%) indicated that the number of squamous cell carcinomas per mouse was decreased by 77% or 88%, and the number of nonmalignant tumors per mouse (primarily keratoacanthomas) was decreased by 56% or 75%, respectively. Topical applications of 6% CSB or 3.6% caffeine inhibited the total number of skin tumor per mouse by 76% or 57%, respectively. Administration of 6% CSB or 3.6% caffeine decreased the volume of squamous cell carcinomas per mouse by 97% or 93%, and the volume of nonmalignant tumors per mouse by 88% or 81%, respectively. Substantial decreases in tumor size per tumor were also observed. Topical applications of CSB in dermabase to tumor-bearing SKH-1 mice (tumors were induced by UVB irradiation) markedly inhibited the growth of these tumors. In tumor-bearing mice treated topically with 6% CSB in dermabase once a day five days a week for 8 weeks, the increase in the number of tumors per mouse was inhibited by 48% and the increase in tumor volume per mouse was inhibited by 68%. Our studies suggest that CSB may be a good preventive agent for UVB-induced carcinogenesis and that CSB may also be a good therapeutic agent on skin tumors (supported in part by NIH Grants No. CA80759 and CA88961).