TY - JOUR
T1 - The antifolate activity of tea catechins
AU - Navarro-Peran, Enma
AU - Durrant, Marcus
AU - Cabezas-Herrera, Juan
AU - Garcia-Canovas, Francisco
AU - Thornley, Roger
AU - Rodriguez-López, José Neptuno
N1 - Durrant's contribution to this multi-author paper was to develop a 3D model for the interaction between epigallocatechin gallate (EGCG) and the dihydrofolate reductase enzyme. We found that EGCG can inhibit the enzyme's normal function, providing an explanation at the molecular level of the anticancer properties of green tea. Reprinted with permission.
PY - 2005/3
Y1 - 2005/3
N2 - A naturally occurring gallated polyphenol isolated from green tea leaves, (−)-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 μmol/L). These data provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in “alternative medicine” as anticarcinogenic/antibiotic agents or in the treatment of conditions such as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (KI = 0.109 μmol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (KI = 10.3 μmol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC50 = 20 μmol/L for EGCG), G0-G1 phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.
AB - A naturally occurring gallated polyphenol isolated from green tea leaves, (−)-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 μmol/L). These data provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in “alternative medicine” as anticarcinogenic/antibiotic agents or in the treatment of conditions such as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (KI = 0.109 μmol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (KI = 10.3 μmol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC50 = 20 μmol/L for EGCG), G0-G1 phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.
KW - Green tea
KW - Epigallocatechin gallate
U2 - 10.1158/0008-5472.CAN-04-3469
DO - 10.1158/0008-5472.CAN-04-3469
M3 - Article
SN - 0008-5472
VL - 65
SP - 2059
EP - 2064
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -