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

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.

• Authors: Andrzej Stepulak, Marco Sifringer, Wojciech Rzeski, Stefanie Endesfelder, Alexander Gratopp, Elena E Pohl, Petra Bittigau, Ursula Felderhoff-Mueser, Angela M Kaindl, Christoph Bührer, Henrik H Hansen, Marta Stryjecka-Zimmer, Lechoslaw Turski, Chrysanthy Ikonomidou
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 43 Pg. 15605-10 (Oct 25 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16230611 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclic AMP Response Element-Binding Protein
• Cyclin-Dependent Kinase Inhibitor p21
• Excitatory Amino Acid Antagonists
• Receptors, N-Methyl-D-Aspartate
• Dizocilpine Maleate
• Extracellular Signal-Regulated MAP Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, 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)