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. 2003 Nov-Dec;5(6):555-65.
doi: 10.1016/s1476-5586(03)80039-8.

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

Anshu Mittal  1 , Chandrika Piyathilake, Yukihiko Hara, Santosh K Katiyar
Affiliations

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

Anshu Mittal et al. Neoplasia. 2003 Nov-Dec.

Abstract

(--)-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.

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Figures

Figure 1
Figure 1
Chemopreventive effects of topical application of EGCG (1 mg/cm2) in hydrophilic cream on UVB-induced skin tumorigenesis in SKH-1 hairless mice. The details of the experimental protocols are described in Materials and Methods section. The percent of mice with tumors (Panel A) and the number of tumors per tumor-bearing mouse (Panel B) were plotted as a function of the number of weeks of treatment. Each treatment group contained 20 mice, and tumor data were recorded until the 24th week of UVB-induced tumor promotion when tumor yield was stabilized. The number of tumors per tumor-bearing mouse has been shown as mean ± SD.
Figure 2
Figure 2
Chemopreventive effects of topical application of EGCG (1 mg/cm2) in hydrophilic cream on UVB-induced malignant transformation of papillomas to carcinomas during UVB-induced skin tumorigenesis protocol in SKH-1 hairless mice. The details of the experiment are described in Materials and Methods section. The percent of mice with carcinomas (Panel A), the number of carcinomas per group (Panel B), and the number of carcinomas per carcinoma-bearing mouse (Panel C) were plotted as a function of the number of weeks of treatment. Each treatment group contained 20 mice, and the number of carcinoma/carcinoma-bearing mouse has been shown as mean ± SD.
Figure 3
Figure 3
Topical application of EGCG in hydrophilic cream inhibits UVB-induced adverse biochemical changes in the skin of SKH-1 hairless mice. H&E staining was performed on skin tissue sections to observe the changes as detailed in Materials and Methods section. Panel A: Normal skin (non-UVB-irradiated). Panel B: UVB-alone-irradiated skin showing hyperplastic response and spongiosis (edematous) in epidermis and dermis, and larger number of infiltrating leukocytes compared to normal skin. Leukocytes are shown by black nuclei. Panel C: UVB-irradiated skin pretreated with EGCG. Treatment of EGCG inhibits UVB-induced hyperplastic response and spongiosis in the epidermis and dermis, and lesser number of infiltrating leukocytes compared to UVB alone. Magnification, x 10.
Figure 4
Figure 4
Topical treatment of EGCG in hydrophilic cream inhibits UVB-induced global DNA hypomethylation pattern in chronically UVB-exposed mouse skin for 30 weeks. Immunohistochemical detection of DNA methylation pattern was performed using anti-5-mc monoclonal antibody as detailed in Materials and Methods section. Panel A: Normal skin (non-UVBexposed). Panel B: UVB irradiation alone. Panel C: EGCG + UVB-irradiated skin. Skin biopsies were subjected to staining for DNA methylation using antibody specific to 5-mc. Cells positive for 5-mc staining appears brown in color. Normal skin showed the presence of numerous positive cells in the epidermis (Panel A) whereas chronic exposure of UVB radiation induced global DNA hypomethylation pattern in the skin (Panel B). Pretreatment with EGCG prevented chronic UVB irradiation-induced global DNA hypomethylation in the skin (Panel C). Magnification, x 40. Panel D: The percentage of cells positive for 5-mc in the epidermis was plotted against different treatment groups as mean ± SD from four animals in each group.
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