(-)-Epigallocatechin-3-gallate (EGCG) has exhibited been studied for
lung cancer inhibitory activity in vitro and in animal models, but it is rapidly methylated and inactivated by
catechol-O-methyltransferase (COMT).
Entacapone and
tolcapone, COMT inhibitors, are used to mitigate the symptoms of
Parkinson's disease. We investigated the synergistic effects of
entacapone/
tolcapone and EGCG against
lung cancer cell lines in culture. EGCG,
entacapone and
tolcapone inhibited the growth of H1299 human
lung cancer cells (IC50 = 174.9, 76.8 and 29.3 µM, respectively) and CL-13 murine
lung cancer cells (IC50 = 181.5, 50.7 and 19.7 µM, respectively) as single agents following treatment for 72h. Treatment with 1:10, 1:5, 1:2.5 and 1:1 combinations of EGCG and
tolcapone or
entacapone resulted in synergistically enhanced growth inhibition. The growth inhibitory effect of the combinations was mediated by induction of intracellular oxidative stress, cell cycle arrest and decreased nuclear translocation of nuclear factor-κΒ. Methylation of EGCG was dose dependently inhibited by
entacapone and
tolcapone (IC50 = 10 and 20 µM, respectively) in a cell-free system, and both compounds increased the intracellular levels of unmethylated EGCG. Treatment of mice with EGCG in combination with
tolcapone increased the bioavailability of EGCG and decreased the methylation of plasma
norepinephrine: no apparent liver or behavioral toxicity was observed. In conclusion, the combination of EGCG and
entacapone/
tolcapone synergistically inhibited the growth of
lung cancer cells in culture, and the mechanistic basis for this synergy is likely due in part to inhibition of COMT with resultant increase in the levels of unmetabolized EGCG.