Repression of Human Hepatocellular Carcinoma Growth by Regulating Met/EGFR/VEGFR-Akt/NF-κB Pathways with Theanine and Its Derivative, (R)-2-(6,8-Dibromo-2-oxo-2H-chromene-3-carboxamido)-5-(ethylamino)-5-oxopentanoic Ethyl Ester (DTBrC)

J Agric Food Chem. 2016 Sep 21;64(37):7002-13. doi: 10.1021/acs.jafc.6b02509. Epub 2016 Sep 9.


To explore the potential of theanine against cancer, we have studied the anticancer activities of theanine from tea and its semisynthesized derivative, (R)-2-(6,8-dibromo-2-oxo-2H-chromene-3-carboxamido)-5-(ethylamino)-5-oxopentanoic ethyl ester (DTBrC), in in vitro, ex vivo, and in vivo models of human hepatocellular carcinoma (HHC). Theanine and DTBrC displayed inhibitory effects on the growth and migration of HHC cells in vitro, ex vivo, and in vivo. Theanine and DTBrC significantly enhanced the repression of HHC cell growth in combination with anticancer drug pirarubicin. Theanine and DTBrC completely suppressed HGF- and EGF+HGF-induced migration with a reduction of p53 tumor suppressor level and enhanced the p53 protein expression in HHC cells. The Akt and NF-κB knockdown greatly reduced cancer cell migration with a decrease in CD44 expression. DTBrC and theanine significantly repressed the protein expressions in the Met/EGFR/VEGFR-Akt/NF-κB pathways, which might be the mechanism for their biologic effects.

Keywords: DTBrC; human hepatocellular carcinoma; inhibition; signaling pathways; theanine.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / physiopathology
  • Cell Movement / drug effects
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Glutamates / administration & dosage*
  • Glutamates / chemistry*
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / physiopathology
  • Molecular Structure
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Vascular Endothelial Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • Glutamates
  • NF-kappa B
  • theanine
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met
  • Receptors, Vascular Endothelial Growth Factor
  • Proto-Oncogene Proteins c-akt