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Type of publication: Journal Article
Type of document: Full Paper

Year: 2005

Authors: Stepulak, A; Sifringer, M; Rzeski, W; Endesfelder, S; Gratopp, A; Pohl, EE; Bittigau, P; Felderhoff-Mueser, U; Kaindl, AM; B├╝hrer, C; Hansen, HH; Stryjecka-Zimmer, M; Turski, L; Ikonomidou, C

Title: NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.

Source: Proc Natl Acad Sci U S A. 2005; 102(43):15605-15610



Authors Vetmeduni Vienna:

Pohl Elena


Abstract:
Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.

Keywords Pubmed: Antineoplastic Agents/pharmacology*
Cell Proliferation/drug effects
Cells, Cultured
Cyclic AMP Response Element-Binding Protein/metabolism
Cyclin-Dependent Kinase Inhibitor p21/genetics
Cyclin-Dependent Kinase Inhibitor p21/physiology
Dizocilpine Maleate/pharmacology*
Excitatory Amino Acid Antagonists/pharmacology*
Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors*
Gene Expression Regulation/drug effects
Humans
Lung Neoplasms/drug therapy
MAP Kinase Signaling System/drug effects*
Phosphorylation
Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors*


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