title: Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas.
abstract: Metabotropic glutamate receptors (mGluR) are predominantly involved in maintenance of cellular homeostasis of central nervous system. However, evidences have suggested other roles of mGluR in human tumors. Aberrant mGluR signaling has been shown to participate in transformation and maintenance of various cancer types, including malignant brain tumors. This review intends to summarize recent findings regarding the involvement of mGluR-mediated intracellular signaling pathways in progression, aggressiveness, and recurrence of malignant gliomas, mainly glioblastomas (GBM), highlighting the potential therapeutic applications of mGluR ligands. In addition to the growing number of studies reporting mGluR gene or protein expression in glioma samples (resections, lineages, and primary cultures), pharmacological blockade in vitro of mGluR1 and mGluR3 by selective ligands has been shown to be anti-proliferative and anti-migratory, decreasing activation of MAPK and PI3K pathways. In addition, mGluR3 antagonists promoted astroglial differentiation of GBM cells and also enabled cytotoxic action of temozolomide (TMZ). mGluR3-dependent TMZ toxicity was supported by increasing levels of MGMT transcripts through an intracellular signaling pathway that sequentially involves PI3K and NF-κB. Further, continuous pharmacological blockade of mGluR1 and mGluR3 have been shown to reduced growth of GBM tumor in two independent in vivo xenograft models. In parallel, low levels of mGluR3 mRNA in GBM resections may be a predictor for long survival rate of patients. Since several Phase I, II and III clinical trials are being performed using group I and II mGluR modulators, there is a strong scientifically-based rationale for testing mGluR antagonists as an adjuvant therapy for malignant brain tumors.
authors.affiliation: Department of Biochemistry, Laboratory of Cellular Neurochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.
authors.forename: Mery Stefani Leivas
authors.initials: MSL
authors.lastname: Pereira
authors.affiliation: Department of Biochemistry, Laboratory of Cellular Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.
authors.forename: Fábio
authors.initials: F
authors.lastname: Klamt
authors.affiliation: Department of Biochemistry, Laboratory of Cellular Neurochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.
authors.forename: Chairini Cássia
authors.initials: CC
authors.lastname: Thomé
authors.affiliation: Department of Neurosurgery, Cristo Redentor Hospital - GHC - Porto Alegre RS, Brazil.|Department of Neurosurgery, São José Hospital, Complexo Hospitalar Santa Casa, Porto Alegre RS, Brazil.
authors.forename: Paulo Valdeci
authors.initials: PV
authors.lastname: Worm
authors.affiliation: Department of Biochemistry, Laboratory of Cellular Neurochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.
authors.forename: Diogo Losch
authors.initials: DL
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D018094:Receptors, Metabotropic Glutamate
keywords: brain cancer; glioblastoma; mGluR