Login Register Cart 0
Current Pharmaceutical Design

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Deciphering the Role of Glutamate Signaling in Glioblastoma Multiforme: Current Therapeutic Modalities and Future Directions

Author(s): Hamid Mollazadehorcid of author, Elmira Mohtashamiorcid of author, Seyed H. Mousaviorcid of author, Mohammad Soukhtanlooorcid of author, Mohammad M. Vahediorcid of author, Azar Hosseini, Amir R. Afshari*orcid of author and Amirhossein Sahebkar*

Volume 26, Issue 37, 2020

Page: [4777 - 4788] Pages: 12

DOI: 10.2174/1381612826666200603132456

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

As the most popular intrinsic neoplasm throughout the brain, glioblastoma multiforme (GBM) is resistant to existing therapies. Due to its invasive nature, GBM shows a poor prognosis despite aggressive surgery and chemoradiation. Therefore, identifying and understanding the critical molecules of GBM can help develop new therapeutic strategies. Glutamatergic signaling dysfunction has been well documented in neurodegenerative diseases as well as in GBM. Inhibition of glutamate receptor activation or extracellular glutamate release by specific antagonists inhibits cell development, invasion, and migration and contributes to apoptosis and autophagy in GBM cells. This review outlines the current knowledge of glutamate signaling involvement and current therapeutic modalities for the treatment of GBM.

Keywords: Glioblastoma multiforme, glutamate, antagonist, invasion, apoptosis, current therapeutic modalities.

« Previous Next »
[1]
Bailly C, Vidal A, Bonnemaire C, et al. Potential for nuclear medicine therapy for glioblastoma treatment. Front Pharmacol 2019; 10: 772.
[http://dx.doi.org/10.3389/fphar.2019.00772 ] [PMID: 31354487]
[2]
Tavana E, Mollazadeh H, Mohtashami E, et al. Quercetin: A promising phytochemical for the treatment of glioblastoma multiforme. Biofactors 2019.
[http://dx.doi.org/10.1002/biof.1605 ] [PMID: 31880372]
[3]
Soukhtanloo M, Mohtashami E, Maghrouni A, et al. Natural products as promising targets in glioblastoma multiforme: a focus on NF-κB signaling pathway. Pharmacol Rep 2020; 72(2): 285-95.
[http://dx.doi.org/10.1007/s43440-020-00081-7 ] [PMID: 32152926]
[4]
Afshari AR, Mollazadeh H, Mohtashami E, et al. Protective role of natural products in glioblastoma multiforme: A focus on nitric oxide pathway. Curr Med Chem 2020.
[http://dx.doi.org/10.2174/0929867327666200130104757 ] [PMID: 32000638]
[5]
Akhavan D, Pourzia AL, Nourian AA, et al. De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. Cancer Discov 2013; 3(5): 534-47.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0502 ] [PMID: 23533263]
[6]
Jalili-Nik M, Sabri H, Zamiri E, et al. Cytotoxic Effects of Ferula Latisecta on Human Glioma U87 Cells. Drug Res (Stuttg) 2019; 69(12): 665-70.
[http://dx.doi.org/10.1055/a-0986-6543 ] [PMID: 31499542]
[7]
Afshari AR, Jalili-Nik M, Soukhtanloo M, et al. Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS). EXCLI J 2019; 18: 576-90.
[PMID: 31611741]
[8]
Miller AM, Shah RH, Pentsova EI, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 2019; 565(7741): 654-8.
[http://dx.doi.org/10.1038/s41586-019-0882-3 ] [PMID: 30675060]
[9]
Zhang X, Zhang W, Mao X-G, Cao W-D, Zhen H-N, Hu S-J. Malignant Intracranial High Grade Glioma and Current Treatment Strategy. Curr Cancer Drug Targets 2019; 19(2): 101-8.
[http://dx.doi.org/10.2174/1568009618666180530090922 ] [PMID: 29848277]
[10]
Karimi Roshan M, Soltani A, Soleimani A, Rezaie Kahkhaie K, Afshari AR, Soukhtanloo M. Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process. Biochimie 2019; 165: 229-34.
[http://dx.doi.org/10.1016/j.biochi.2019.08.003 ] [PMID: 31401189]
[11]
Afshari AR, Karimi Roshan M, Soukhtanloo M, et al. Cytotoxic effects of auraptene against a human malignant glioblastoma cell line. Avicenna J Phytomed 2019; 9(4): 334-46.
[PMID: 31309072]
[12]
Suárez-Pozos E, Thomason EJ, Fuss B. Glutamate Transporters: Expression and Function in Oligodendrocytes. Neurochem Res 2020; 45(3): 551-60.
[PMID: 30628017]
[13]
Xiao B, Chen D, Zhou Q, et al. Glutamate metabotropic receptor 4 (GRM4) inhibits cell proliferation, migration and invasion in breast cancer and is regulated by miR-328-3p and miR-370-3p. BMC Cancer 2019; 19(1): 891.
[http://dx.doi.org/10.1186/s12885-019-6068-4 ] [PMID: 31492116]
[14]
Buckingham SC, Campbell SL, Haas BR, et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med 2011; 17(10): 1269-74.
[http://dx.doi.org/10.1038/nm.2453 ] [PMID: 21909104]
[15]
Takano T, Lin JH-C, Arcuino G, Gao Q, Yang J, Nedergaard M. Glutamate release promotes growth of malignant gliomas. Nat Med 2001; 7(9): 1010-5.
[http://dx.doi.org/10.1038/nm0901-1010 ] [PMID: 11533703]
[16]
Yuen TI, Morokoff AP, Bjorksten A, et al. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology 2012; 79(9): 883-9.
[http://dx.doi.org/10.1212/WNL.0b013e318266fa89 ] [PMID: 22843268]
[17]
de Groot J, Sontheimer H. Glutamate and the biology of gliomas. Glia 2011; 59(8): 1181-9.
[http://dx.doi.org/10.1002/glia.21113 ] [PMID: 21192095]
[18]
Sontheimer H. Malignant gliomas: perverting glutamate and ion homeostasis for selective advantage. Trends Neurosci 2003; 26(10): 543-9.
[http://dx.doi.org/10.1016/j.tins.2003.08.007 ] [PMID: 14522147]
[19]
Simões AP, Silva CG, Marques JM, et al. Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death Dis 2018; 9(3): 297.
[http://dx.doi.org/10.1038/s41419-018-0351-1 ] [PMID: 29463792]
[20]
Sontheimer H. A role for glutamate in growth and invasion of primary brain tumors. J Neurochem 2008; 105(2): 287-95.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05301.x ] [PMID: 18284616]
[21]
Budczies J, Pfitzner BM, Györffy B, et al. Glutamate enrichment as new diagnostic opportunity in breast cancer. Int J Cancer 2015; 136(7): 1619-28.
[http://dx.doi.org/10.1002/ijc.29152 ] [PMID: 25155347]
[22]
Rose CR, Felix L, Zeug A, Dietrich D, Reiner A, Henneberger C. Astroglial glutamate signaling and uptake in the hippocampus. Front Mol Neurosci 2018; 10: 451.
[http://dx.doi.org/10.3389/fnmol.2017.00451 ] [PMID: 29386994]
[23]
Dalley CB, Wroblewska B, Wolfe BB, Wroblewski JT. The role of metabotropic glutamate receptor 1 dependent signaling in glioma viability. J Pharmacol Exp Ther 2018; 367(1): 59-70.
[http://dx.doi.org/10.1124/jpet.118.250159 ] [PMID: 30054311]
[24]
Nedergaard M. Treatment of glial tumors with glutamate antagonists. Google Patents 2007.
[25]
Robert SM, Sontheimer H. Glutamate transporters in the biology of malignant gliomas. Cell Mol Life Sci 2014; 71(10): 1839-54.
[http://dx.doi.org/10.1007/s00018-013-1521-z ] [PMID: 24281762]
[26]
Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 2007; 67(19): 9463-71.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-2034 ] [PMID: 17909056]
[27]
Venkataramani V, Tanev DI, Strahle C, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 2019; 573(7775): 532-8.
[http://dx.doi.org/10.1038/s41586-019-1564-x ] [PMID: 31534219]
[28]
van Lith SA, Navis AC, Verrijp K, et al. Glutamate as chemotactic fuel for diffuse glioma cells: are they glutamate suckers? Biochim Biophys Acta 2014; 1846(1): 66-74.
[PMID: 24747768]
[29]
Sribnick EA, Ray SK, Banik NL. Estrogen prevents glutamate-induced apoptosis in C6 glioma cells by a receptor-mediated mechanism. Neuroscience 2006; 137(1): 197-209.
[http://dx.doi.org/10.1016/j.neuroscience.2005.08.074 ] [PMID: 16289585]
[30]
Sørensen MF, Heimisdóttir SB, Sørensen MD, et al. High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma. J Neurooncol 2018; 138(1): 49-53.
[http://dx.doi.org/10.1007/s11060-018-2785-9 ] [PMID: 29404978]
[31]
Thomas AG, Sattler R, Tendyke K, et al. High-throughput assay development for cystine-glutamate antiporter (xc-) highlights faster cystine uptake than glutamate release in glioma cells. PLoS One 2015; 10(8) e0127785
[http://dx.doi.org/10.1371/journal.pone.0127785 ] [PMID: 26252954]
[32]
de Groot JF, Liu TJ, Fuller G, Yung WK. The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Res 2005; 65(5): 1934-40.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3626 ] [PMID: 15753393]
[33]
Bianchi MG, Gazzola GC, Tognazzi L, Bussolati O. C6 glioma cells differentiated by retinoic acid overexpress the glutamate transporter excitatory amino acid carrier 1 (EAAC1). Neuroscience 2008; 151(4): 1042-52.
[http://dx.doi.org/10.1016/j.neuroscience.2007.11.055 ] [PMID: 18207650]
[34]
Yang W, Kilberg MS. Biosynthesis, intracellular targeting, and degradation of the EAAC1 glutamate/aspartate transporter in C6 glioma cells. J Biol Chem 2002; 277(41): 38350-7.
[http://dx.doi.org/10.1074/jbc.M202052200 ] [PMID: 12151387]
[35]
Nagane M, Kanai E, Shibata Y, et al. Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma. PLoS One 2018; 13(4) e0195151
[http://dx.doi.org/10.1371/journal.pone.0195151 ] [PMID: 29649284]
[36]
Sleire L, Skeie BS, Netland IA, et al. Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion. Oncogene 2015; 34(49): 5951-9.
[http://dx.doi.org/10.1038/onc.2015.60 ] [PMID: 25798841]
[37]
Chung WJ, Sontheimer H. Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB. J Neurochem 2009; 110(1): 182-93.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06129.x ] [PMID: 19457125]
[38]
Khan AJ, LaCava S, Mehta M, et al. The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget 2019; 10(29): 2824-34.
[http://dx.doi.org/10.18632/oncotarget.26854 ] [PMID: 31073373]
[39]
Gladwin A, Peng S, Kiefer J, Kim S, Berens M, Dhruv HD. mGluR1 drives invasion of proneural subtype of glioblastoma cells. AACR 2017.
[40]
Koochekpour S, Majumdar S, Azabdaftari G, et al. Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells. Clin Cancer Res 2012; 18(21): 5888-901.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1308 ] [PMID: 23072969]
[41]
Koochekpour S. Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer. Asian J Androl 2013; 15(2): 212-3.
[http://dx.doi.org/10.1038/aja.2012.145 ] [PMID: 23314660]
[42]
Shin SS, Namkoong J, Wall BA, Gleason R, Lee HJ, Chen S. Oncogenic activities of metabotropic glutamate receptor 1 (Grm1) in melanocyte transformation. Pigment Cell Melanoma Res 2008; 21(3): 368-78.
[http://dx.doi.org/10.1111/j.1755-148X.2008.00452.x ] [PMID: 18435704]
[43]
Marín YE, Chen S. Involvement of metabotropic glutamate receptor 1, a G protein coupled receptor, in melanoma development. J Mol Med (Berl) 2004; 82(11): 735-49.
[http://dx.doi.org/10.1007/s00109-004-0566-8 ] [PMID: 15322701]
[44]
Ohtani Y, Harada T, Funasaka Y, et al. Metabotropic glutamate receptor subtype-1 is essential for in vivo growth of melanoma. Oncogene 2008; 27(57): 7162-70.
[http://dx.doi.org/10.1038/onc.2008.329 ] [PMID: 18776920]
[45]
Namkoong J, Shin S-S, Lee HJ, et al. Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma. Cancer Res 2007; 67(5): 2298-305.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3665 ] [PMID: 17332361]
[46]
Le MN, Chan JL-K, Rosenberg SA, et al. The glutamate release inhibitor Riluzole decreases migration, invasion, and proliferation of melanoma cells. J Invest Dermatol 2010; 130(9): 2240-9.
[http://dx.doi.org/10.1038/jid.2010.126 ] [PMID: 20505744]
[47]
Khan AJ, Wall B, Ahlawat S, et al. Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res 2011; 17(7): 1807-14.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-1276 ] [PMID: 21325066]
[48]
Mehnert JM, Silk AW, Lee JH, et al. A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma. Pigment Cell Melanoma Res 2018; 31(4): 534-40.
[http://dx.doi.org/10.1111/pcmr.12694 ] [PMID: 29453787]
[49]
Shin SS, Wall BA, Goydos JS, Chen S. AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1). Pigment Cell Melanoma Res 2010; 23(1): 103-11.
[http://dx.doi.org/10.1111/j.1755-148X.2009.00648.x ] [PMID: 19843246]
[50]
Yu LJ, Wall BA, Wangari-Talbot J, Chen S. Metabotropic glutamate receptors in cancer. Neuropharmacology 2017; 115: 193-202.
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.011 ] [PMID: 26896755]
[51]
Mao L-M, Wang JQ. Regulation of group I metabotropic glutamate receptors by MAPK/ERK in neurons. J Nat Sci 2016; 2(12): 2.
[PMID: 28008418]
[52]
Speyer CL, Smith JS, Banda M, DeVries JA, Mekani T, Gorski DH. Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer. Breast Cancer Res Treat 2012; 132(2): 565-73.
[http://dx.doi.org/10.1007/s10549-011-1624-x ] [PMID: 21681448]
[53]
Banda M, Speyer CL, Semma SN, et al. Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer. PLoS One 2014; 9(1) e81126
[http://dx.doi.org/10.1371/journal.pone.0081126 ] [PMID: 24404125]
[54]
Speyer CL, Hachem AH, Assi AA, Johnson JS, DeVries JA, Gorski DH. Metabotropic glutamate receptor-1 as a novel target for the antiangiogenic treatment of breast cancer. PLoS One 2014; 9(3) e88830
[http://dx.doi.org/10.1371/journal.pone.0088830 ] [PMID: 24633367]
[55]
Speyer CL, Nassar MA, Hachem AH, et al. Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1. Breast Cancer Res Treat 2016; 157(2): 217-28.
[http://dx.doi.org/10.1007/s10549-016-3816-x ] [PMID: 27146584]
[56]
Dolfi SC, Medina DJ, Kareddula A, et al. Riluzole exerts distinct antitumor effects from a metabotropic glutamate receptor 1-specific inhibitor on breast cancer cells. Oncotarget 2017; 8(27): 44639-53.
[http://dx.doi.org/10.18632/oncotarget.17961 ] [PMID: 28591718]
[57]
Zhang C, Yuan XR, Li HY, et al. Anti-cancer effect of metabotropic glutamate receptor 1 inhibition in human glioma U87 cells: involvement of PI3K/Akt/mTOR pathway. Cell Physiol Biochem 2015; 35(2): 419-32.
[http://dx.doi.org/10.1159/000369707 ] [PMID: 25613036]
[58]
Teh JL, Shah R, La Cava S, et al. Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells. Breast Cancer Res Treat 2015; 151(1): 57-73.
[http://dx.doi.org/10.1007/s10549-015-3365-8 ] [PMID: 25859923]
[59]
Nicoletti F, Bruno V, Ngomba RT, Gradini R, Battaglia G. Metabotropic glutamate receptors as drug targets: what’s new? Curr Opin Pharmacol 2015; 20: 89-94.
[http://dx.doi.org/10.1016/j.coph.2014.12.002 ] [PMID: 25506748]
[60]
Park S-Y, Lee SA, Han I-H, et al. Clinical significance of metabotropic glutamate receptor 5 expression in oral squamous cell carcinoma. Oncol Rep 2007; 17(1): 81-7.
[http://dx.doi.org/10.3892/or.17.1.81 ] [PMID: 17143482]
[61]
Choi KY, Chang K, Pickel JM, Badger JD II, Roche KW. Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice. Proc Natl Acad Sci USA 2011; 108(37): 15219-24.
[http://dx.doi.org/10.1073/pnas.1107304108 ] [PMID: 21896768]
[62]
Abdallah CG, Hannestad J, Mason GF, et al. Metabotropic glutamate receptor 5 and glutamate involvement in major depressive disorder: a multimodal imaging study. Biol Psychiatry Cogn Neurosci Neuroimaging 2017; 2(5): 449-56.
[http://dx.doi.org/10.1016/j.bpsc.2017.03.019 ] [PMID: 28993818]
[63]
Luyt K, Varadi A, Halfpenny CA, Scolding NJ, Molnar E. Metabotropic glutamate receptors are expressed in adult human glial progenitor cells. Biochem Biophys Res Commun 2004; 319(1): 120-9.
[http://dx.doi.org/10.1016/j.bbrc.2004.04.158 ] [PMID: 15158450]
[64]
Liu B, Zhao S, Qi C, et al. Inhibition of metabotropic glutamate receptor 5 facilitates hypoxia-induced glioma cell death. Brain Res 2019; 1704: 241-8.
[http://dx.doi.org/10.1016/j.brainres.2018.10.021 ] [PMID: 30347216]
[65]
Tilleux S, Berger J, Hermans E. Induction of astrogliosis by activated microglia is associated with a down-regulation of metabotropic glutamate receptor 5. J Neuroimmunol 2007; 189(1-2): 23-30.
[http://dx.doi.org/10.1016/j.jneuroim.2007.06.011 ] [PMID: 17628702]
[66]
Koehl A, Hu H, Feng D, et al. Structural insights into the activation of metabotropic glutamate receptors. Nature 2019; 566(7742): 79-84.
[http://dx.doi.org/10.1038/s41586-019-0881-4 ] [PMID: 30675062]
[67]
Pereira MSL, Klamt F, Thomé CC, Worm PV, de Oliveira DL. Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas. Oncotarget 2017; 8(13): 22279-98.
[http://dx.doi.org/10.18632/oncotarget.15299 ] [PMID: 28212543]
[68]
Bocchio M, Lukacs IP, Stacey R, et al. Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex. Front Cell Neurosci 2019; 12: 508.
[PMID: 30670948]
[69]
Wang X, Prager BC, Wu Q, et al. Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell Stem Cell 2018; 22: 514-28.
[http://dx.doi.org/10.1016/j.stem.2018.03.011]
[70]
Zhou K, Song Y, Zhou W, et al. mGlu3 receptor blockade inhibits proliferation and promotes astrocytic phenotype in glioma stem cells. Cell Biol Int 2014; 38(4): 426-34.
[http://dx.doi.org/10.1002/cbin.10207 ] [PMID: 24482010]
[71]
Corsi L, Mescola A, Alessandrini A. Glutamate receptors and glioblastoma multiforme: an old “route” for new perspectives. Int J Mol Sci 2019; 20(7): 1796.
[http://dx.doi.org/10.3390/ijms20071796 ] [PMID: 30978987]
[72]
Ciceroni C, Arcella A, Mosillo P, et al. Type-3 metabotropic glutamate receptors negatively modulate bone morphogenetic protein receptor signaling and support the tumourigenic potential of glioma-initiating cells. Neuropharmacology 2008; 55(4): 568-76.
[http://dx.doi.org/10.1016/j.neuropharm.2008.06.064 ] [PMID: 18621067]
[73]
D’Onofrio M, Arcella A, Bruno V, et al. Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. J Neurochem 2003; 84(6): 1288-95.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01633.x ] [PMID: 12614329]
[74]
Arcella A, Carpinelli G, Battaglia G, et al. Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Neuro-oncol 2005; 7(3): 236-45.
[http://dx.doi.org/10.1215/S1152851704000961 ] [PMID: 16053698]
[75]
Schunemann DP, Grivicich I, Regner A, et al. Glutamate promotes cell growth by EGFR signaling on U-87MG human glioblastoma cell line. Pathol Oncol Res 2010; 16(2): 285-93.
[http://dx.doi.org/10.1007/s12253-009-9223-4 ] [PMID: 19997873]
[76]
Hombach-Klonisch S, Mehrpour M, Shojaei S, et al. Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 2018; 184: 13-41.
[http://dx.doi.org/10.1016/j.pharmthera.2017.10.017 ] [PMID: 29080702]
[77]
Ciceroni C, Bonelli M, Mastrantoni E, et al. Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas. Cell Death Differ 2013; 20(3): 396-407.
[http://dx.doi.org/10.1038/cdd.2012.150 ] [PMID: 23175182]
[78]
De Santis MC, Gulluni F, Campa CC, Martini M, Hirsch E. Targeting PI3K signaling in cancer: Challenges and advances. Biochimica et Biophysica Acta (BBA)-. Rev Can 2019; 1871: 361-6.
[79]
Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 2009; 69(20): 7986-93.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2266 ] [PMID: 19826036]
[80]
Yelskaya Z, Carrillo V, Dubisz E, Gulzar H, Morgan D, Mahajan SS. Synergistic inhibition of survival, proliferation, and migration of U87 cells with a combination of LY341495 and Iressa. PLoS One 2013; 8(5) e64588
[http://dx.doi.org/10.1371/journal.pone.0064588 ] [PMID: 23724064]
[81]
da Hora CC, Pinkham K, Carvalho L, et al. Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition. Cell Death Discov 2019; 5: 72.
[http://dx.doi.org/10.1038/s41420-019-0155-9 ] [PMID: 30854231]
[82]
Jiang L, Song L, Wu J, et al. Bmi-1 promotes glioma angiogenesis by activating NF-κB signaling. PLoS One 2013; 8(1) e55527
[http://dx.doi.org/10.1371/journal.pone.0055527 ] [PMID: 23383216]
[83]
Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem 2016; 109: 314-41.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.012 ] [PMID: 26807863]
[84]
Lin C-J, Chen T-L, Tseng Y-Y, et al. Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. Toxicol Appl Pharmacol 2016; 304: 59-69.
[http://dx.doi.org/10.1016/j.taap.2016.05.018 ] [PMID: 27236003]
[85]
Chinnaiyan P, Won M, Wen PY, et al. RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma International Journal of Radiation Oncology* Biology* Physics 2013; 86: 880-4..
[86]
Pissimissis N, Papageorgiou E, Lembessis P, Armakolas A, Koutsilieris M. The glutamatergic system expression in human PC-3 and LNCaP prostate cancer cells. Anticancer Res 2009; 29(1): 371-7.
[PMID: 19331175]
[87]
Li T, Huang Y, Chen X, et al. Metabotropic glutamate receptor 8 activation promotes the apoptosis of lung carcinoma A549 cells in vitro. [Acta physiologica Sinica] 2015; 67: 513-20..
[88]
Chang HJ, Yoo BC, Lim S-B, Jeong S-Y, Kim WH, Park J-G. Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance. Clin Cancer Res 2005; 11(9): 3288-95.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1912 ] [PMID: 15867225]
[89]
Yang W, Maolin H, Jinmin Z, Zhe W. High expression of metabotropic glutamate receptor 4: correlation with clinicopathologic characteristics and prognosis of osteosarcoma. J Cancer Res Clin Oncol 2014; 140(3): 419-26.
[http://dx.doi.org/10.1007/s00432-013-1581-3 ] [PMID: 24399291]
[90]
Zhang Z, Zheng X, Luan Y, et al. Activity of metabotropic glutamate receptor 4 suppresses proliferation and promotes apoptosis with inhibition of Gli-1 in human glioblastoma cells. Front Neurosci 2018; 12: 320.
[http://dx.doi.org/10.3389/fnins.2018.00320 ] [PMID: 29867331]
[91]
Jantas D, Grygier B, Gołda S, Chwastek J, Zatorska J, Tertil M. An endogenous and ectopic expression of metabotropic glutamate receptor 8 (mGluR8) inhibits proliferation and increases chemosensitivity of human neuroblastoma and glioma cells. Cancer Lett 2018; 432: 1-16.
[http://dx.doi.org/10.1016/j.canlet.2018.06.004 ] [PMID: 29885518]
[92]
Yao HH, Ding JH, Zhou F, et al. Enhancement of glutamate uptake mediates the neuroprotection exerted by activating group II or III metabotropic glutamate receptors on astrocytes. J Neurochem 2005; 92(4): 948-61.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02937.x ] [PMID: 15686497]
[93]
van Vuurden DG, Yazdani M, Bosma I, et al. Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment. PLoS One 2009; 4(6) e5953
[http://dx.doi.org/10.1371/journal.pone.0005953 ] [PMID: 19536293]
[94]
Ishiuchi S, Yoshida Y, Sugawara K, et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci 2007; 27(30): 7987-8001.
[http://dx.doi.org/10.1523/JNEUROSCI.2180-07.2007 ] [PMID: 17652589]
[95]
Sheng M, Lee SH. AMPA receptor trafficking and the control of synaptic transmission. Cell 2001; 105(7): 825-8.
[http://dx.doi.org/10.1016/S0092-8674(01)00406-8 ] [PMID: 11439178]
[96]
de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK. Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol 2008; 88(2): 121-33.
[http://dx.doi.org/10.1007/s11060-008-9552-2 ] [PMID: 18317690]
[97]
Beretta F, Bassani S, Binda E, et al. The GluR2 subunit inhibits proliferation by inactivating Src-MAPK signalling and induces apoptosis by means of caspase 3/6-dependent activation in glioma cells. Eur J Neurosci 2009; 30(1): 25-34.
[http://dx.doi.org/10.1111/j.1460-9568.2009.06804.x ] [PMID: 19558602]
[98]
Ishiuchi S, Tsuzuki K, Yoshida Y, et al. Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med 2002; 8(9): 971-8.
[http://dx.doi.org/10.1038/nm746 ] [PMID: 12172541]
[99]
Schroeter H, Bahia P, Spencer JP, et al. (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. J Neurochem 2007; 101(6): 1596-606.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04434.x ] [PMID: 17298385]
[100]
Oh MC, Kim JM, Safaee M, et al. Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PLoS One 2012; 7(10) e47846
[http://dx.doi.org/10.1371/journal.pone.0047846 ] [PMID: 23110111]
[101]
Ramaswamy P, Nanjaiah ND, Prasad C, Goswami K. Transcriptional modulation of calcium-permeable AMPA receptor subunits in glioblastoma by MEK-ERK1/2 inhibitors and their role in invasion. Cell Biol Int 2019.
[PMID: 31814223]
[102]
Piao Y, Lu L, de Groot J. AMPA receptors promote perivascular glioma invasion via β1 integrin-dependent adhesion to the extracellular matrix. Neuro-oncol 2009; 11(3): 260-73.
[http://dx.doi.org/10.1215/15228517-2008-094 ] [PMID: 18957620]
[103]
Mayer J, Kirschstein T, Resch T, et al. Perampanel attenuates epileptiform phenotype in C6 glioma. Neurosci Lett 2020. 715134629
[http://dx.doi.org/10.1016/j.neulet.2019.134629 ] [PMID: 31734290]
[104]
Lange F, Weßlau K, Porath K, et al. AMPA receptor antagonist perampanel affects glioblastoma cell growth and glutamate release in vitro. PLoS One 2019; 14(2) e0211644
[http://dx.doi.org/10.1371/journal.pone.0211644 ] [PMID: 30716120]
[105]
Grossman SA, Ye X, Chamberlain M, et al. Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial. J Clin Oncol 2009; 27(25): 4155-61.
[http://dx.doi.org/10.1200/JCO.2008.21.6895 ] [PMID: 19636006]
[106]
Iwamoto FM, Kreisl TN, Kim L, et al. Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer 2010; 116(7): 1776-82.
[http://dx.doi.org/10.1002/cncr.24957 ] [PMID: 20143438]
[107]
Liu K-H, Yang S-T, Lin Y-K, et al. Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis. Oncotarget 2015; 6(7): 5088-101.
[http://dx.doi.org/10.18632/oncotarget.3243 ] [PMID: 25671301]
[108]
Wang XY, Li YL, Wang HY, et al. Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca2+ permeable AMPA receptor-system xc- pathway. Toxicol In Vitro 2017; 44: 57-65.
[http://dx.doi.org/10.1016/j.tiv.2017.06.026 ] [PMID: 28663055]
[109]
Wang X, Wang H, Wang G, Yang Z, Zhang T. Effects of propofol on invasion and migration of glioma cells in rats and the role of ADAR2-AMPA receptor GluR2 pathway. Chinese Journal of Anesthesiology 2016; 36: 712-5.
[110]
Yang C, Wang H, Xia Z, et al. Propofol suppresses oxidative stress in gliomas through down-regulating divalent metal transporter 1. Br J Anaesth 2019; 122: e40-1.
[http://dx.doi.org/10.1016/j.bja.2018.10.018]
[111]
Walczak K, Deneka-Hannemann S, Jarosz B, et al. Kynurenic acid inhibits proliferation and migration of human glioblastoma T98G cells. Pharmacol Rep 2014; 66(1): 130-6.
[http://dx.doi.org/10.1016/j.pharep.2013.06.007 ] [PMID: 24905318]
[112]
Stepulak A, Sifringer M, Rzeski W, et al. NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. Proc Natl Acad Sci USA 2005; 102(43): 15605-10.
[http://dx.doi.org/10.1073/pnas.0507679102 ] [PMID: 16230611]
[113]
Deutsch SI, Tang AH, Burket JA, Benson AD. NMDA receptors on the surface of cancer cells: target for chemotherapy? Biomed Pharmacother 2014; 68(4): 493-6.
[http://dx.doi.org/10.1016/j.biopha.2014.03.012 ] [PMID: 24751001]
[114]
Müller-Längle A, Lutz H, Hehlgans S, Rödel F, Rau K, Laube B. NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells-A Potential Target for Adjuvant Radiotherapy. Cancers (Basel) 2019; 11(4): 503.
[http://dx.doi.org/10.3390/cancers11040503 ] [PMID: 30970642]
[115]
Nandakumar DN, Ramaswamy P, Prasad C, Srinivas D, Goswami K. Glioblastoma invasion and NMDA receptors: A novel prospect. Physiol Int 2019; 106(3): 250-60.
[http://dx.doi.org/10.1556/2060.106.2019.22 ] [PMID: 31564120]
[116]
North WG, Liu F, Dragnev KH, Demidenko E. Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy. Clin Pharmacol 2019; 11: 15-23.
[http://dx.doi.org/10.2147/CPAA.S183885 ] [PMID: 30774453]
[117]
Duan W, Hu J, Liu Y. Ketamine inhibits colorectal cancer cells malignant potential via blockage of NMDA receptor. Exp Mol Pathol 2019; 107: 171-8.
[http://dx.doi.org/10.1016/j.yexmp.2019.02.004 ] [PMID: 30817910]
[118]
Noch E, Khalili K. Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity. Cancer Biol Ther 2009; 8(19): 1791-7.
[http://dx.doi.org/10.4161/cbt.8.19.9762 ] [PMID: 19770591]
[119]
Yoon W-S, Yeom M-Y, Kang E-S, Chung Y-A, Chung D-S, Jeun S-S. Memantine induces NMDAR1-mediated autophagic cell death in malignant glioma cells. J Korean Neurosurg Soc 2017; 60(2): 130-7.
[http://dx.doi.org/10.3340/jkns.2016.0101.006 ] [PMID: 28264232]
[120]
Maraka S, Groves MD, Mammoser AG, et al. Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer 2019; 125(3): 424-33.
[http://dx.doi.org/10.1002/cncr.31811 ] [PMID: 30359477]
[121]
Lefranc F, Le Rhun E, Kiss R, Weller M. Glioblastoma quo vadis: Will migration and invasiveness reemerge as therapeutic targets? Cancer Treat Rev 2018; 68: 145-54.
[http://dx.doi.org/10.1016/j.ctrv.2018.06.017 ] [PMID: 30032756]
[122]
Cacciatore I, Fornasari E, Marinelli L, et al. Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma. Eur J Pharm Sci 2017; 109: 402-11.
[http://dx.doi.org/10.1016/j.ejps.2017.08.030 ] [PMID: 28860082]
[123]
Kasemsuk T, Kaeopu R, Yubolphan R, Phuagkhaopong S, Vivithanaporn P. Apoptotic and antiproliferative effects of amantadine and rimantadine in glioblastoma cells. Thai J Pharm Sci 2019; 43(3)
[124]
Stepulak A, Rola R, Polberg K, Ikonomidou C. Glutamate and its receptors in cancer. J Neural Transm (Vienna) 2014; 121(8): 933-44.
[http://dx.doi.org/10.1007/s00702-014-1182-6 ] [PMID: 24610491]
[125]
Ramaswamy P, Aditi Devi N, Hurmath Fathima K, Dalavaikodihalli Nanjaiah N. Activation of NMDA receptor of glutamate influences MMP-2 activity and proliferation of glioma cells. Neurol Sci 2014; 35(6): 823-9.
[http://dx.doi.org/10.1007/s10072-013-1604-5 ] [PMID: 24374786]
[126]
Gomes FCA, Sousa Vde O, Romão L. Emerging roles for TGF-β1 in nervous system development. Int J Dev Neurosci 2005; 23(5): 413-24.
[http://dx.doi.org/10.1016/j.ijdevneu.2005.04.001 ] [PMID: 15936920]
[127]
Han J, Alvarez-Breckenridge CA, Wang Q-E, Yu J. TGF-β signaling and its targeting for glioma treatment. Am J Cancer Res 2015; 5(3): 945-55.
[PMID: 26045979]
[128]
Liu C-C, Wu S-N, Sze C-I. The potential role of NMDA receptor regulating TGF-β/Smad pathway in radiation-induced resistance in glioblastoma multiforme. The FASEB Journal 2017; 31: 934.
[129]
Rösche J, Piek J, Hildebrandt G, Grossmann A, Kirschstein T, Benecke R. [Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation. Fortschr Neurol Psychiatr 2015; 83(5): 286-9.
[PMID: 26018396]
[130]
Di Bonaventura C, Labate A, Maschio M, Meletti S, Russo E. AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives. Expert Opin Pharmacother 2017; 18(16): 1751-64.
[http://dx.doi.org/10.1080/14656566.2017.1392509 ] [PMID: 29023170]
[131]
Caumont A-S, Octave J-N, Hermans E. Amantadine and memantine induce the expression of the glial cell line-derived neurotrophic factor in C6 glioma cells. Neurosci Lett 2006; 394(3): 196-201.
[http://dx.doi.org/10.1016/j.neulet.2005.10.027 ] [PMID: 16298481]
[132]
Yohay K, Tyler B, Weaver KD, et al. Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models. J Neurosurg 2014; 120(4): 854-63.
[http://dx.doi.org/10.3171/2013.12.JNS13641 ] [PMID: 24484234]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 28
Html icon 1
Find your institution