cfm-2 and Lung-Neoplasms

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.

Topics: Adenocarcinoma; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Antineoplastic Agents; Benzodiazepines; Benzodiazepinones; Cell Cycle; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Activation; Excitatory Amino Acid Antagonists; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Receptors, AMPA; Signal Transduction