|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Medical Neuro-Oncology |
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.
References
Aronica, E., Gorter, J.A., Ijlst-Keizers, H., Rozemuller, A.J., Yankaya, B., Leenstra, S., and Troost, D. (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: Opposite regulation of glutamate transporter proteins. Eur. J. Neurosci. 17,2106 -2118.[CrossRef][ISI][Medline]
Battaglia, G., Bruno, V., Ngomba, R.T., Di Grezia, R., Copani, A., and Nico letti, F. (1998) Selective activation of group-II metabotropic glutamate receptors is protective against excitotoxic neuronal death. Eur. J. Pharmacol. 356,271 -274.[CrossRef][ISI][Medline]
Bowman, C.L., Yohe, L., and Lohr, J.W. (1999) Enzymatic modulation of cell volume in C6 glioma cells. Glia 27,22 -31.[CrossRef][ISI][Medline]
Bredel, M., and Zentner, J. (2002) Brain-tumour drug resistance: The bare essentials. Lancet Oncol. 3, 397-406.[CrossRef][Medline]
Bruno, V., Battaglia, G., Copani, A., D'Onofrio, M., Di Iorio, P., De Blasi, A., Melchiorri, D., Flor, P.J., and Nicoletti F. (2001) Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J. Cereb. Blood Flow Metab. 21,1013 -1033.[ISI][Medline]
Burnashev, N., Monyer, H., Seeburg, P.H., and Sakmann, B. (1992) Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8,189 -198.[CrossRef][ISI][Medline]
Condorelli, D.F., Dell'Albani, P., Corsaro, M., Giuffrida, R., Caruso, A., Trovato Salinaro, A., Spinella, F., Nicoletti, F., Albanese, V., and Giuf frida Stella, A. (1997) Metabotropic glutamate receptor expression in cultured rat astrocytes and human gliomas. Neurochem. Res. 22,1127 -1133.[CrossRef][ISI][Medline]
Copani, A., Condorelli, F., Caruso, A., Cancheri, C., Sala, A.,
Giuffrida Stella, A.M., Canonico, P.L., Nicoletti, F., and Sortino, M.A.
(1999) Mitotic signaling by beta-amyloid causes neuronal death.
FASEB J. 13,2225
-2234.
D'Onofrio, M., Cuomo, L., Battaglia, G., Ngomba, R.T., Storto, M., Kingston, A.E., Orzi, F., De Blasi, A., Di Iorio, P., Nicoletti, F., and Bruno, V. (2001) Neuroprotection mediated by group-II metabotropic glutamate receptors requires the activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. J. Neurochem. 78,435 -445.[CrossRef][ISI][Medline]
D'Onofrio, M., Arcella, A., Bruno, V., Ngomba, R.T., Battaglia, G., Lombari, V., Ragona, G., Calogero, A., and Nicoletti, F. (2003) Pharmacologi cal blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. J. Neurochem. 84,1288 -1295.[CrossRef][ISI][Medline]
Franklin, K.B.J., and Paxinos, G. (1997) The Mouse Brain in Stereotaxic Coordinates. San Diego, Calif.: Academic Press.
Giese, A. (2003) Glioma invasion—pattern of dissemination by mechanisms of invasion and surgical intervention, pattern of gene expression and its regulatory control by tumor suppressor p53 and proto-oncogene ETS-1. Acta Neurochir. Suppl. 88,153 -162.
Ishiuchi, S., Tsuzuki, K., Yoshida, Y., Yamada, N., Hagimura, N., Okado, H., Miwa, A., Kurihara, H., Nakazato, Y., Tamura, M., Sasaki, T., and Osawa, S. (2002) Blockade of Ca2+ permeable AMPA receptors sup presses migration and induces apoptosis in human glioblastoma cells. Nat. Med. 8,971 -978.[CrossRef][ISI][Medline]
Jane, D.E., Thomas, N.K., Tse, H.W., and Watkins, J.C. (1996) Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord. Neuropharmacology 35,1029 -1035.[CrossRef][ISI][Medline]
Johnson, B.G., Wright, R.A., Arnold, M.B., Wheeler, W.J., Ornstein, P.L., and Schoepp, D.D. (1999) [3H]-LY341495 as a novel antagonist radio-ligand for group II metabotropic glutamate (mGlu) receptors: Charac terization of binding to membranes of mGlu receptor subtype express ing cells. Neuropharmacology 38,1519 -1529.[CrossRef][ISI][Medline]
Kingston, A.E., O'Neill, M.J., Lam, A., Bales, K.R., Monn, J.A., and Scho epp, D.D. (1999) Neuroprotection by metabotropic glutamate receptor agonists LY354740, LY379268 and LY389795. Eur. J. Pharmacol. 377,155 -165.[CrossRef][ISI][Medline]
Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., and Schoepp, D.D. (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37,1 -12.[CrossRef][ISI][Medline]
Monn, J.A., Valli, M.J., Massey, S.M., Hansen, M.M., Kress, T.J., Wepsiec, J.P., Harkness, A.R., Grutsch, J.L., Jr., Wright, R.A., Johnson, B.G., Andis, S.L., Kingston, A., Tomlinson, R., Lewis, R., Griffey, K.R., Tiz zano, J.P., and Schoepp, D.D. (1999) Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): Identification of two new potent, selective, and systemi cally active agonists for group II metabotropic glutamate receptors. J. Med. Chem. 42,1027 -1040.[CrossRef][ISI][Medline]
Poli, A., Beraudi, A., Villani, L., Storto, M., Battaglia, G., Di
Giorgi Gerevini, V., Cappuccio, I., Caricasole, A., D'Onofrio, M., and
Nicoletti, F. (2003) Group II metabotropic glutamate receptors
regulate the vulnerability to hypoxic brain damage. J.
Neurosci. 23,6023
-6029.
Reichelt, W., Stabel-Burow, J., Pannicke, T., Weichert, H., and Heinemann, U. (1997) The glutathione level of retinal Muller glial cells is dependent on the high-affinity sodium-dependent uptake of glutamate. Neuroscience 77,1213 -1224.[CrossRef][ISI][Medline]
Rzeski, W., Turski, L., and Ikonomidou, C. (2001) Glutamate antagonists limit tumor growth. Proc. Natl. Acad. Sci. USA 11,6372 -6377.
Sallese, M., Iacovelli, L., Storto, M., and De Blasi, A. (2001) Receptor speci ficity of G-protein-coupled receptor kinases in target cells. Trends Pharmacol. Sci. 22, 168-169 (letter).[Medline]
Schoepp, D.D., Jane, D.E., and Monn, J.A. (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38,1431 -1476.[CrossRef][ISI][Medline]
Sommer, B., Kohler, M., Sprengel, R., and Seeburg, P.H. (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated chan nels. Cell 67, 11-19.[CrossRef][ISI][Medline]
Sontheimer, H. (2003) Malignant gliomas: Perverting glutamate and ion homeostasis for selective advantage. Trends Neurosci. 26,543 -549.[CrossRef][ISI][Medline]
Takano, T., Lin, J.H., Arcuino, G., Gao, Q., Yang, J., and Nedergaard, M. (2001) Glutamate release promotes growth of malignant gliomas. Nat. Med. 7,1010 -1015.[CrossRef][ISI][Medline]
Ye, Z.C., Rothstein, J.D., and Sontheimer, H. (1999)
Compromised glutamate transport in human glioma cells:
Reduction-mislocalization of sodium-dependent glutamate transporters and
enhanced activity of cysteine-glutamate exchange. J.
Neurosci. 19,10767
-10777.
Ye, Z.C., and Sontheimer, H. (1999) Glioma cells
release excitotoxic con centrations of glutamate. Cancer
Res. 59,4383
-4391.
This article has been cited by other articles:
|
|
 |
|
  Y.-S. Fu, Y.-Y. Lin, S.-C. Chou, T.-H. Tsai, L.-S. Kao, S.-Y. Hsu, F.-C. Cheng, Y.-H. Shih, H. Cheng, Y.-Y. Fu, et al. Tetramethylpyrazine inhibits activities of glioma cells and glutamate neuro-excitotoxicity: Potential therapeutic application for treatment of gliomas Neuro-oncol, April 1, 2008; 10(2): 139 - 152. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
