AMPA antagonists inhibit the extracellular signal regulated kinase pathway and suppress lung cancer growth

Cancer Biol Ther. 2007 Dec;6(12):1908-15. doi: 10.4161/cbt.6.12.4965. Epub 2007 Sep 1.

Abstract

Antagonists at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors limit growth of human cancers in vitro. However, the mechanism of anticancer action of AMPA antagonists is not known. Here we report that the AMPA antagonists GYKI 52466 and CFM-2 inhibit the extracellular signal regulated kinase (ERK1/2) pathway, an intracellular signaling cascade which is activated by growth factors and controls proliferation of lung adenocarcinoma cells. AMPA antagonists reduced phosphorylation of cAMP-responsive element binding protein (CREB), suppressed expression of cyclin D1, upregulated the cell cycle regulators and tumor suppressor proteins p21 and p53 and decreased number of lung adenocarcinoma cells in G2 and S phases of the cell cycle. These findings reveal potential mechanism of antiproliferative action of AMPA antagonists and indicate that this class of compounds may be useful in the therapy of human cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Antineoplastic Agents / pharmacology
  • Benzodiazepines / pharmacology*
  • Benzodiazepinones / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Drug Screening Assays, Antitumor
  • Enzyme Activation / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology*
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Receptors, AMPA / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Benzodiazepinones
  • CFM 2
  • Excitatory Amino Acid Antagonists
  • Neoplasm Proteins
  • Receptors, AMPA
  • GYKI 52466
  • Benzodiazepines
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3