EXECUTIVE SUMMARY

Caffeine Sodium Benzoate – A Novel Agent for

Inhibiting Sunlight-Induced Skin Cancer

SUMMARY:  Dr. Allan H. Conney in the Ernest Mario School of Pharmacy at Rutgers University has found that topical administration of caffeine sodium benzoate can be used for the prevention of UVB light-induced skin cancer even after stopping exposure to the UVB light.  Caffeine and caffeine sodium benzoate are the first examples of compounds that have both sunscreen activity and selectively enhance the killing of UVB damaged skin cells.  This combination of effects may provide benefits beyond those observed for simple sunscreen agents; caffeine and caffeine sodium benzoate continue to work even after stopping exposure to the UVB light.

BACKGROUND:  Research findings from several laboratories have revealed that administration of caffeine results in inhibition of carcinogenesis in several animal models.  The caffeine molecule absorbs the 280-320nm (UVB) portion of UV light.  Earlier research indicated that topical applications of caffeine during the course of UVB treatment inhibited UVB-induced skin cancer in mice.  Subsequent research by Dr. Conney demonstrated that caffeine could inhibit UVB-induced carcinogenesis by both a sunscreen effect as well as by selectively killing DNA damaged skin cells.  Additionally, Dr. Conney has been exploring various novel formulations for caffeine to arrive at a highly efficacious formulation for the treatment of sun-induced skin cancer. 

TECHNOLOGY: 

The research findings from Dr. Conney’s lab unequivocally point to a proapoptotic effect of caffeine for prevention of UVB-induced skin carcinogenesis.  The salient points of the findings are the following:

• Research from several laboratories indicates that a family of enzymes, commonly referred to as “caspases”, play a pivotal role in the initiation and execution of programmed cell death (apoptosis).  Caspase-3 (active form) is an excellent biomarker of apoptosis.  Based on this observation, Dr. Conney’s lab studied the effect of topical applications of caffeine on apoptosis by counting the number of caspase-3 positive cells using an immunohistochemical assay.

• It was found that topical applications of caffeine immediately after UVB irradiation resulted in enhanced UVB-induced increases in apoptotic cells in the epidermis of SKH-1 hairless mice but not in normal non-irradiated epidermis.  Utilizing this finding, a routine assay was established to measure the relative efficacy of topical applications of the new caffeine formulations.

• With the discovery of the enhancement of caffeine on UVB-induced apoptosis, Dr. Conney has been advancing his research to discover more potent/efficacious formulations of caffeine for the prevention of skin cancer.

• Using the above-mentioned assays, caffeine sodium benzoate was found to be superior to caffeine.

• More recent data has been acquired in chronic animal studies.  Mice were exposed to UVB irradiation for 20 weeks followed by a 17 week UVB-free incubation period when the animals developed skin tumors.  After stopping UVB, control UVB-pretreated mice without tumors were treated topically once a day 5 days a week with a vehicle cream (control mice) or with caffeine sodium benzoate in the cream.  After 17 weeks of topical applications, control mice had 12 tumors per mouse whereas the caffeine sodium benzoate treated mice had only 3 tumors per mouse.  Treatment of the mice with caffeine sodium benzoate decreased the percentage of mice with squamous cell carcinomas by 78%, and tumor volume per mouse for squamous cell carcinomas was decreased by 93%.  Thus, in this in-vivo model, the highly beneficial effects of caffeine sodium benzoate for the prevention of skin cancer were demonstrated.

• In another study using SKH-1 hairless mice, topical application of caffeine sodium benzoate in a dermatological cream 30 min. before UVB irradiation inhibited the formation of thymine dimers in DNA and inhibited by 83% UVB-induced skin sunburn lesions when compared with control mice exposed to UVB light.  This experiment demonstrates the possibility of prevention of sun-induced skin cancer by caffeine sodium benzoate through the mechanism of a sun-screening effect in addition to the proapoptotic effect.

PATENT STATUS:  United States Patent Application No. 20050207998 entitled “Caffeine Salt Complexes and Methods for using the same in the Prevention or Treatment of Cancer” was filed on June 20, 2004 and published on September 22, 2005.

PUBLICATIONS:  Some of the results above have recently been published:  Y-P. Lu, Y-U. Lou, J-G, Xie, Q-Y Peng, S. Zhou, Y. Lin, W. J. Shih and A. H. Conney, Caffeine and Caffeine Sodium Benzoate have a Sunscreen Effect, Enhance UVB-Induced Apoptosis, and Inhibit UVB-Induced Skin Carcinogenesis in SKH-1 Mice, Carcinogenesis, 28 (1), 199-206 (2007).