Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells

• Published in: Journal of neurochemistry Vol. 84; no. 6; pp. 1288 - 1295
• Main Authors: D'Onofrio, Mara, Arcella, Antonietta, Bruno, Valeria, Ngomba, Richard T., Battaglia, Giuseppe, Lombari, Vincenza, Ragona, Giuseppe, Calogero, Antonella, Nicoletti, Ferdinando
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-03-2003; Blackwell
• Subjects: Amino Acids - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Division - drug effects; Cells, Cultured; cyclin D1; Cyclin D1 - metabolism; Cyclin D2; Cyclins - metabolism; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; glial proliferation; glioma; Glioma - drug therapy; Glioma - metabolism; Humans; MAP kinase; Medical sciences; mGlu receptors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Neurology; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Thymidine - pharmacokinetics; Tritium; Tumors of the nervous system. Phacomatoses; Xanthenes - pharmacology; Human; Cell proliferation; Nervous system diseases; Glial cell; mGlu receptors; Enzyme; Neuroglia; Glioblastoma; glial proliferation; Mitogen-activated protein kinase; MAP kinase; Malignant tumor; In vitro; mglu2 glutamate receptor; mglu3 glutamate receptor; Group II mglu glutamate receptor; Malignant glioma; Metabotropic receptor; Central nervous system disease; Cell cycle; glioma; cyclin D1
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01633.x

Glial cell proliferation in culture is under the control of metabotropic glutamate (mGlu) receptors. We have examined whether this control extends to human glioma cells. Primary cultures were prepared from surgically removed human glioblastomas. RT‐PCR combined with western blot analysis showed that most of the cultures (eight out of 11) expressed group‐II mGlu receptors. In two selected cultures (MZC‐12 and FCN‐9), the mGlu2/3 receptor antagonist, LY341495, slowed cell proliferation when applied to the growth medium from the second day after plating. This effect was reversible because linear cell growth was restored after washing out the drug. LY341495 reduced glioma cell proliferation at concentrations lower than 100 nm, which are considered as selective for mGlu2/3 receptors. In addition, its action was mimicked by the putative mGlu2/3 receptor antagonist (2S)‐α‐ethylglutamate. The anti‐proliferative effect of LY341495 was confirmed by measuring [methyl‐3H]‐thymidine incorporation in cultures arrested in G0 phase of the cell cycle and then stimulated to proliferate by the addition of 10% fetal calf serum or 100 ng/mL of epidermal growth factor (EGF). In cultures treated with EGF, LY341495 was also able to reduce the stimulation of the mitogen‐activated protein kinase (MAPK) pathway, as well as the induction of cyclin D1. Both effects, as well as decreased [methyl‐3H]‐thymidine incorporation, were partially reduced by co‐addition of the potent mGlu2/3 receptor agonist, LY379268. We conclude that activation of group‐II mGlu receptors supports the growth of human glioma cells in culture and that antagonists of these receptors should be tested for their ability to reduce tumour growth in vivo.