Synergistic inhibition of lung cancer cell lines by (-)-epigallocatechin-3-gallate in combination with clinically used nitrocatechol inhibitors of catechol-O-methyltransferase

Sarah C. Forester, Joshua D. Lambert

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18 Citations (Scopus)

Abstract

(-)-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 72 h. 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-κB. 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.

Original languageEnglish (US)
Article numberbgt347
Pages (from-to)365-372
Number of pages8
JournalCarcinogenesis
Volume35
Issue number2
DOIs
StatePublished - Feb 1 2014

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Lung Neoplasms
Cell Line
Inhibitory Concentration 50
Catechol O-Methyltransferase
Growth
Methylation
Catechol O-Methyltransferase Inhibitors
epigallocatechin gallate
nitrocatechol
Cell-Free System
Cell Cycle Checkpoints
tolcapone
Biological Availability
Parkinson Disease
entacapone
Norepinephrine
Oxidative Stress
Animal Models
Cell Culture Techniques
Liver

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

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title = "Synergistic inhibition of lung cancer cell lines by (-)-epigallocatechin-3-gallate in combination with clinically used nitrocatechol inhibitors of catechol-O-methyltransferase",
abstract = "(-)-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 72 h. 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-κB. 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.",
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AU - Lambert, Joshua D.

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N2 - (-)-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 72 h. 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-κB. 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.

AB - (-)-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 72 h. 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-κB. 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.

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