Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice.
Tea polyphenolic constituents induce apoptosis in cancer cells but not in normal cells. To study the mechanism of this selective effect, we used the ornithine decarboxylase (ODC)/Ras double transgenic mouse model that develops spontaneous skin tumors due to over-expression of 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 with 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 over-expressing 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 with 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, pre-neoplastic stages of cancer having higher levels of polyamines.
Paul
Barry
B
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Hayes
Candace S
CS
Kim
Arianna
A
Athar
Mohammad
M
Gilmour
Susan K
SK
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015317:Biogenic Polyamines / Q000032:analysis / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D011905:Genes, ras; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000235:genetics; D012878:Skin Neoplasms / Q000517:prevention & control*; D018631:ras Proteins / Q000235:genetics
D016588:Anticarcinogenic Agents; D015317:Biogenic Polyamines; D002392:Catechin; C045651:epigallocatechin gallate; D018631:ras Proteins; D009955:Ornithine Decarboxylase