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Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate

Cancer 2001 Feb 15;91(4):822-32               

Garbisa S; Sartor L; Biggin S; Salvato B ; Benelli R; Albini A
Department of Experimental Biomedical Sciences, Medical School, University of Padova, viale G. Colombo 3, 35121 Padova, Italy. garbisa@civ.bio.unipd.it .

BACKGROUND: Given the association of consumption of green tea with prevention of cancer development, metastasis, and angiogenesis, the effect of the main flavanol present, epigallocatechin-3-gallate (EGCG), on two gelatinases most frequently overexpressed in cancer and angiogenesis (MMP-2 and MMP-9) and on tumor cell invasion and chemotaxis were examined.
METHODS: Zymography, Western blotting, and enzyme linked immuoadsorbent assay were used to analyze the effect of EGCG on MMP-2 and MMP-9 activity, whereas its effect on tumor cell invasion and chemotaxis was examined using modified Boyden chamber assays.
RESULTS: A Zn2+ chelation-independent, dose-dependent, noncompetitive inhibition by EGCG of both gelatinases was found at concentrations 500 times lower than that reported to inhibit urokinase. Tumor cell invasion of a reconstituted basement membrane matrix, but not chemotaxis, was reduced by 50% with EGCG concentrations equivalent to that in the plasma of moderate green tea drinkers, and 2 orders of magnitude below those of tissue inhibitors of MMPs. Although higher concentrations of EGCG were associated with increased levels of both cell-associated gelatinases and their activator MT1-MMP, no increased gelatinase activation was found, and TIMP-1 and TIMP-2 inhibitors were up-regulated. Finally, concentrations of EGCG active in restraining proliferation and inducing apoptosis of transformed cells were more than 100 times lower than those reported for normal cells.
CONCLUSIONS: Epigallocatechin-3-gallate is a potent inhibitor of gelatinases and an orally available pharmacologic agent that may confer the antiangiogenic and antimetastatic activity associated with green tea.



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