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Carcinogenesis Advance Access published online on September 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh281
© 2004 by Oxford University Press
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Received June 3, 2004
Revised August 5, 2004
Accepted September 5, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice1

Barry Paul 1, Candace S. Hayes 1, Arianna Kim 2, Mohammad Athar 2, and Susan K. Gilmour 1*

1 Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096
2 Department of Dermatology, Columbia University, 630W 168th St, New York, New York 10032

* To whom correspondence should be addressed. E-mail: gilmours{at}mlhs.org.


  Abstract

Tea polyphenolic constituents induce apoptosis in cancer cells but not in normal cells. To study the mechanism of this selective effect, we used the ODC/Ras double transgenic mouse model that develops spontaneous skin tumors due to overexpression of ornithine decarboxylase (ODC) and a v-Ha-ras transgene. Administration of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the drinking water significantly decreased both tumor number and total tumor burden compared to untreated ODC/Ras mice without decreasing the elevated polyamine levels present in the ODC/Ras mice. EGCG selectively decreased both proliferation and survival of primary cultures of ODC overexpressing transgenic keratinocytes but not keratinocytes from normal littermates nor ras-infected keratinocytes. This decreased survival was due to EGCG-induced apoptosis and not terminal differentiation. Moreover, in skin from EGCG-treated ODC transgenic mice, caspase 3 (active form) was detected only in epidermal cells that possess very high levels of ODC protein. Since most transformed cells and tumor tissue possess higher levels of polyamines compared to normal cells or tissue, our data suggest that the elevated levels of polyamines in tumor cells sensitize them to EGCG-induced apoptosis. These results suggest that EGCG may be an effective chemopreventive agent in individuals with early, preneoplastic stages of cancer having higher levels of polyamines.

Keywords: polyamines; ornithine decarboxylase; (-)-epigallocatechin-3-gallate; skin carcinogenesis; apoptosis.

1 Supported by grants CA070739 and CA97249 from the National Cancer Institute


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