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Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo

I.N.M. Neuromed, Località Camerelle, 86077 Pozzilli (A.A., G.B., M.D., R.T.N., V.B., F.G., F.N.); Department of Cellular Biology and Neuroscience (G.C., F.S.), Istituto Superiore di Sanità, 00161 Rome; Departments of Human Physiology and Pharmacology (V.B., P.C., F.N.) and Experimental Medicine and Pathology (F.G.), University of Rome La Sapienza, 00185 Rome; Italy

⁴ Address correspondence to Ferdinando Nicoletti, Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italy (ferdinandonicoletti{at}hotmail.com).

Abstract

U87MG human glioma cells in cultures expressed metabotropic glutamate (mGlu) receptors mGlu2 and mGlu3. Addition of the mGlu2/3 receptor antagonist LY341495 to the cultures reduced cell growth, expression of cyclin D1/2, and activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. This is in line with the evidence that activation of mGlu2/3 receptors sustains glioma cell proliferation. U87MG cells were either implanted under the skin (1 x 10⁶ cells/0.5 ml) or infused into the caudate nucleus (0.5 x 10⁶ cells/5 µl) of nude mice. Animals were treated for 28 days with mGlu receptor antagonists by means of subcutaneous osmotic minipumps. Treatments with LY341495 or (2S)--ethylglutamate (both infused at a rate of 1 mg/kg per day) reduced the size of tumors growing under the skin. Infusion of LY341495 (10 mg/kg per day) also reduced the growth of brain tumors, as assessed by magnetic resonance imaging analysis carried out every seven days. The effect of drug treatment was particularly evident during the exponential phase of tumor growth, that is, between the third and the fourth week following cell implantation. Immunohistochemical analysis showed that U87MG cells retained the expression of mGlu2/3 receptors when implanted into the brain of nude mice. These data suggest that mGlu2/3 receptor antagonists are of potential use in the experimental treatment of malignant gliomas.

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