title: Ionotropic glutamate receptor antagonists and cancer therapy: time to think out of the box?
abstract: Glutamate has a trophic function in the development of the central nervous system, regulating the proliferation and migration of neuronal progenitors. The resemblance between neuronal embryonic and tumor cells has paved the way for the investigation of the effects of glutamate on tumor cells. Indeed, tumor cells derived from neuronal tissue express ionotropic glutamate receptor (iGluRs) subunits and iGluR antagonists decrease cell proliferation. Likewise, iGluRs subunits are expressed in several peripheral cancer cells and blockade of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptor subtypes decreases their proliferation and migration. Although these mechanisms are still being investigated, the inhibition of the mitogen-activated protein kinase pathway was shown to play a key role in the antiproliferative activity of iGluR antagonists. Importantly, MK-801, a NMDAR channel blocker, was effective and well tolerated in animal models of melanoma, lung, and breast cancers, suggesting that the blockade of iGluR signaling may represent a new strategy for cancer treatment. In this review, we focus on the significance of NMDA and AMPA receptor expression in tumor cells, as well as possible therapeutic strategies targeting these receptors.
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354, Coimbra, Portugal.|Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors: Mariana P C
authors: MP
authors: Ribeiro
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354, Coimbra, Portugal.|Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors: José B A
authors: JB
authors: Custódio
authors: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354, Coimbra, Portugal. aesantos@ci.uc.pt.|Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal. aesantos@ci.uc.pt.
authors: Armanda E
authors: AE
authors: Santos
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D018091:Receptors, AMPA; D058468:Receptors, Ionotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate
keywords: AMPA receptors; Cancer; Glutamate; NMDA receptors