Exceptionally high protection of photocarcinogenesis by topical application of (--)-epigallocatechin-3-gallate in hydrophilic cream in SKH-1 hairless mouse model: relationship to inhibition of UVB-induced global DNA hypomethylation.

(--)-Epigallocatechin-3-gallate (EGCG) has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic cream as a vehicle for EGCG. Treatment with EGCG ( approximately 1 mg/cm(2) skin area) in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKH-1 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB)-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVB-induced global DNA hypomethylation pattern. Long-term application of EGCG did not show any apparent sign of toxicity in mice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.