Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1

Carcinogenesis. 2007 Sep;28(9):1918-27. doi: 10.1093/carcin/bgm110. Epub 2007 Aug 11.

Abstract

Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non-flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is approximately 30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells. Myricetin (10 microM) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 microM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fireflies / enzymology
  • Flavonoids / pharmacology*
  • Genes, Reporter
  • Luciferases / genetics
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / genetics
  • Mice
  • Recombinant Proteins / antagonists & inhibitors
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Flavonoids
  • Recombinant Proteins
  • Epidermal Growth Factor
  • myricetin
  • Luciferases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Tetradecanoylphorbol Acetate