Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice.

Irradiation of female SKH-1 hairless mice with UVB (30 mJ/cm2) twice a week for 10-20 weeks resulted in the formation of a large number of cellular patches (>8 adjacent cells/patch) that are recognized with an antibody (Pab240) which recognizes mutated but not wild-type p53 protein. These patches are not recognized by an antibody (Pab1620) to wild-type p53 protein. The patches, which are considered putative early cellular markers of the beginning of tumor formation, started appearing after 4-6 weeks of UVB treatment, and multiple patches were observed after treatment for 10 weeks. The number and size of the patches increased progressively with continued UVB treatment. Discontinuation of UVB for 4 weeks resulted in an 80-90% decrease in the number of these patches. The number of the remaining patches did not decrease any further but remained relatively constant for at least 4-9 weeks. Oral administration of green tea (6 mg tea solids/ml) or caffeine (0.4 mg/ml) as the sole source of drinking fluid during irradiation with UVB, twice a week for 20 weeks, inhibited UVB-induced formation of mutant p53 positive patches by approximately 40%. Oral administration of green tea (6 mg tea solids/ml) as the sole source of drinking fluid or topical applications of caffeine (6.2 micromol) once a day 5 days a week starting immediately after discontinuation of UVB treatment enhanced the rate and extent of disappearance of the mutant p53-positive patches. Topical applications of caffeine to the dorsal skin of mice pretreated with UVB for 20 weeks resulted in enhanced apoptosis selectively in focal basal cell hyperplastic areas of the epidermis (putative precancerous lesions), but not in areas of the epidermis that only had diffuse hyperplasia. Our studies indicate that the chemopreventive effect of caffeine or green tea may occur by a proapoptotic effect preferentially in early precancerous lesions.

[1]  Y. Lou,et al.  Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice. , 2005, Carcinogenesis.

[2]  F. Pontén,et al.  Mutation spectra of epidermal p53 clones adjacent to basal cell carcinoma and squamous cell carcinoma , 2004, Experimental dermatology.

[3]  Y. Lou,et al.  Stimulatory Effect of Topical Application of Caffeine on UVB-Induced Apoptosis in the Epidermis of p53 and Bax Knockout Mice , 2004, Cancer Research.

[4]  A. Eastman.  Cell cycle checkpoints and their impact on anticancer therapeutic strategies , 2004, Journal of cellular biochemistry.

[5]  Y. Lou,et al.  Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Harris,et al.  The IARC TP53 database: New online mutation analysis and recommendations to users , 2002, Human mutation.

[7]  J. Griffith,et al.  Preferential binding of ATR protein to UV-damaged DNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Schreiber,et al.  ATR Is Not Required for p53 Activation but Synergizes with p53 in the Replication Checkpoint* , 2002, The Journal of Biological Chemistry.

[9]  D. Zelterman,et al.  Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Schreiber,et al.  ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Gruijl,et al.  Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity. , 2001, Cancer research.

[12]  D. Brash,et al.  Stimulatory effect of oral administration of green tea or caffeine on ultraviolet light-induced increases in epidermal wild-type p53, p21(WAF1/CIP1), and apoptotic sunburn cells in SKH-1 mice. , 2000, Cancer research.

[13]  Y. P. Lu,et al.  Time course for early adaptive responses to ultraviolet B light in the epidermis of SKH-1 mice. , 1999, Cancer research.

[14]  J. Sarkaria,et al.  Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. , 1999, Cancer research.

[15]  A. Kumagai,et al.  The Xenopus Chk1 Protein Kinase Mediates a Caffeine-sensitive Pathway of Checkpoint Control in Cell-free Extracts , 1998, The Journal of cell biology.

[16]  Y. P. Lu,et al.  Inhibitory effect of black tea on the growth of established skin tumors in mice: effects on tumor size, apoptosis, mitosis and bromodeoxyuridine incorporation into DNA. , 1997, Carcinogenesis.

[17]  F. Pontén,et al.  Molecular pathology in basal cell cancer with p53 as a genetic marker , 1997, Oncogene.

[18]  N. Dumaz,et al.  The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice. , 1997, Carcinogenesis.

[19]  R. Gascoyne,et al.  Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. , 1997, Cancer research.

[20]  R. Tarone,et al.  Frequent clones of p53-mutated keratinocytes in normal human skin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  F. Gruijl,et al.  Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Friend,et al.  Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. , 1995, Cancer research.

[23]  R Montesano,et al.  Database of p53 gene somatic mutations in human tumors and cell lines. , 1994, Nucleic acids research.

[24]  A. Ziegler,et al.  Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[25]  B L Diffey,et al.  Solar ultraviolet radiation effects on biological systems. , 1991, Physics in medicine and biology.

[26]  A. Young.  The sunburn cell. , 1987, Photo-dermatology.

[27]  B. Diffey,et al.  Natural UV‐B radiation received by people with outdoor, indoor, and mixed occupations and UV‐B treatment of psoriasis , 1983, Clinical and experimental dermatology.

[28]  W. Lobitz,et al.  Histochemical responses of human skin following ultraviolet irradiation. , 1961, The Journal of investigative dermatology.

[29]  Y. Lou,et al.  Stimulatory effect of topical application of caffeine on UVB-induced apoptosis in mouse skin. , 2002, Oncology research.

[30]  T. Jacks,et al.  Sunburn and p53 in the onset of skin cancer , 1994, Nature.