Glioma and Neurokinin-1 Receptor Antagonists: A New Therapeutic Approach

Author(s): Miguel Muñoz*, Rafael Coveñas.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: In adults, the most lethal and frequent primary brain tumor is glioblastoma. Despite multimodal aggressive therapies, the median survival time after diagnosis is around 15 months. In part, this is due to the blood-brain barrier that restricts common treatments (e.g., chemotherapy). Unfortunately, glioma recurs in 90% of patients. New therapeutic strategies against glioma are urgently required. Substance P (SP), through the neurokinin (NK)-1 receptor, controls cancer cell proliferation by activating c-myc, mitogenactivated protein kinases, activator protein 1 and extracellular signal-regulated kinases 1 and 2. Glioma cells overexpress NK-1 receptors when compared with normal cells. The NK-1 receptor/SP system regulates the proliferation/migration of glioma cells and stimulates angiogenesis, triggering inflammation which contributes to glioma progression. In glioma cells, SP favors glycogen breakdown, essential for glycolysis. By contrast, in glioma, NK-1 receptor antagonists block the proliferation of tumor cells and the breakdown of glycogen and also promote the death (apoptosis) of these cells. These antagonists also inhibit angiogenesis and exert antimetastatic and anti-inflammatory actions.

Objective: This review updates the involvement of the NK-1 receptor/SP system in the development of glioma and the potential clinical application of NK-1 receptor antagonists as antiglioma agents.

Conclusion: The NK-1 receptor plays a crucial role in glioma and NK-1 receptor antagonists could be used as anti-glioma drugs.

Keywords: Substance P, glioblastoma, aprepitant, antitumor, apoptosis, metastasis, angiogenesis, signalling pathway.

Davis, F.G.; Freels, S.; Grutsch, J.; Barlas, S.; Brem, S. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type. An analysis based on surveillance, epidemiology, and end results (SEER) data. 1973-1991. J. Neurosurg., 1998, 88, 1-10.
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O. European organisation for research and treatment of cancer brain tumor and radiotherapy groups; national cancer institute of canada clinical trials group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med., 2005, 352, 987-996.
Alifieris, C.; Trafalis, D.T. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol. Ther., 2015, 152, 63-82.
Hamard, L.; Ratel, D.; Selek, L.; Berger, F.; van der Sanden, B.; Wion, D. The brain tissue response to surgical injury and its possible contribution to glioma recurrence. J. Neurooncol., 2016, 128, 1-8.
Frosina, G. Limited advances in therapy of glioblastoma trigger re-consideration of research policy. Crit. Rev. Oncol. Hematol., 2015, 96, 257-261.
Møller, H.G.; Rasmussen, A.P.; Andersen, H.H.; Johnsen, K.B.; Henriksen, M.; Duroux, M. A systematic review of microRNA in glioblastoma multiforme: Micro-modulators in the mesenchymal mode of migration and invasion. Mol. Neurobiol., 2013, 47(1), 131-144.
Chandran, M.; Candolfi, M.; Shah, D.; Mineharu, Y.; Yadav, V.; Koschmann, C.; Asad, A.S.; Lowenstein, P.R.; Castro, M.G. Single vs. combination immunotherapeutic strategies for glioma. Expert Opin. Biol. Ther., 2017, 20, 1-12.
Reifenberger, G.; Wirsching, H.G.; Knobbe-Thomsen, C.B.; Weller, M. Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat. Rev. Clin. Oncol., 2016.
Drapeau, A.; Fortin, D. Chemotherapy delivery strategies to the central nervous system: Neither optional nor superfluous. Curr. Cancer Drug Targets, 2015, 15, 752-768.
Chen, Y.; Xu, R. Drug repurposing for glioblastoma based on molecular subtypes. J. Biomed. Inform., 2016, 64, 131-138.
Muñoz, M.; Coveñas, R.; Esteban, F.; Redondo, M. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J. Biosci., 2015, 40, 441-463.
Hökfelt, T.; Broberger, C.; David Xu, Z-Q.; Sergeyev, V.; Ubink, R.; Díez, M. Neuropeptides: An overview. Neuropharmacology, 2000, 39, 1337-1356.
Li, Y.; Douglas, S.D.; Ho, W. Human stem cells express substance P gene and its receptor. J. Hematother. Stem Cell Res., 2000, 9, 445-452.
Dubon, M.J.; Park, K.S. Substance P enhances the proliferation and migration potential of murine bone marrow-derived mesenchymal stem cell-like cell lines. Exp. Ther. Med., 2015, 9, 1185-1191.
Kim, K.T.; Kim, H.J.; Cho, D.C.; Bae, J.S.; Park, S.W. Substance P stimulates proliferation of spinal neural stem cells in spinal cord injury via the mitogen-activated protein kinase signaling pathway. Spine J., 2015, 15, 2055-2065.
Garnier, A.; Vykoukal, J.; Hubertus, J.; Alt, E.; von Schweinitz, D.; Kappler, R.; Berger, M.; Ilmer, M. Targeting the neurokinin-1 receptor inhibits growth of human colon cancer cells. Int. J. Oncol., 2015, 47, 151-160.
Kalkan, R. Glioblastoma stem cells as a new therapeutic target for glioblastoma. Clin. Med. Insights Oncol., 2015, 9, 95-103.
Wang, J.; Ma, Y.; Cooper, M.K. Cancer stem cells in glioma: challenges and opportunities. Transl. Cancer Res., 2013, 2, 429-441.
Walczak-Drzewiecka, A.; Ratajewski, M.; Wagner, W.; Dastych, J. HIF-1alpha is up-regulated in activated mast cells by a process that involves calcineurin and NFAT. J. Immunol., 2008, 181, 1665-1672.
Muñoz, M.; Roso, M.; González-Ortega, A.; Sáenz, J.; Coveñas, R. The broad-spectrum antitumor action of cyclosporin A is due to its tachykinin receptor antagonist pharmacological profile. Peptides, 2010, 31, 1643-1648.
Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor cancer progression. Peptides, 2013, 48, 1-9.
Ogo, H.; Kuroyanagi, N.; Inoue, A.; Nishio, H.; Hirai, Y.; Akiyama, M.; DiMaggio, D.A.; Krause, J.E.; Nakata, Y. Human astrocytoma cells (U-87 MG) exhibit a specific substance P-binding site with the characteristics of an NK-1 receptor. J. Neurochem., 1996, 67, 1813-1820.
Palma, C.; Nardelli, F.; Manzini, S.; Maggi, C.A. Substance P activates responses correlated with tumor growth in human glioma cell lines bearing tachykinin NK1 receptors. Br. J. Cancer, 1999, 79, 236-243.
Berger, A.; Paige, C.J. Hemokinin-1 has substance P-like function in U-251 MG astrocytoma cells. A pharmacological and functional study. J. Neuroimmunol., 2005, 164, 48-56.
Muñoz, M.; Rosso, M.; Pérez, A.; Coveñas, R.; Rosso, R.; Zamarriego, C.; Piruat, J.I. The NK1 receptor is involved in the antitumoral action of L-733,060 and the mitogenic action of substance P on neuroblastoma and glioma cell lines. Neuropeptides, 2005, 39, 427-432.
Fowler, C.J.; Brännström, G. Substance P enhances forskolin-stimulated cyclic AMP production in human UC-11MG astrocytoma cells. Methods Find. Exp. Clin. Pharmacol., 1994, 16, 21-28.
Hennig, I.M.; Laissue, J.A.; Horisberger, U.; Reubi, J.C. Substance-P receptors in human primary neoplasms: Tumoral and vascular localization. Int. J. Cancer, 1995, 61, 786-792.
Friess, H.; Zhu, Z.; Liard, V.; Shi, X.; Shrikhande, S.V.; Wang, L.; Lieb, K.; Korc, M.; Palma, C.; Zimmermann, A.; Reubi, J.C.; Büchler, M.W. Neurokinin-1 recep-tor expression and its potential effects on tumor growth in human pancreatic cancer. Lab. Invest., 2003, 83, 731-742.
Luo, W.; Sharif, T.R.; Sharif, M. Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated proteína kinase signaling pathway. Cancer Res., 1996, 56, 4983-4991.
Muñoz, M.; Rosso, M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest. New Drugs, 2010, 28, 187-193.
Sporn, M.B. The war on cancer. Lancet, 1996, 347, 1377-1381.
Lang, K.; Drell, T.L.; Lindecke, A.; Niggemann, B.; Kaltschmidt, C.; Zaenker, K.S.; Entschladen, F. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int. J. Cancer, 2004, 112, 231-238.
Fackler, O.T.; Grosse, R. Cell motility through plasma membrane blebbing. J. Cell Biol., 2008, 181, 879-884.
Meshki, J.; Douglas, S.D.; Hu, M.; Leeman, S.E.; Tuluc, F.P. Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner. PLoS One, 2011, 6, e25332.
Mou, L.; Kang, Y.; Zhou, Y.; Zeng, Q.; Song, H.; Wang, R. Neurokinin-1 receptor directly mediates glioma cell migration by up-regulation of matrix metalloproteinase-2 (MMP-2) and membrane type 1-matrix metalloproteinase (MT1-MMP). J. Biol. Chem., 2013, 288, 306-318.
Ziche, M.; Morbidelli, L.; Pacini, M.; Gepetti, P.; Alessandri, G.; Maggi, C.A. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc. Res., 1990, 40, 264-278.
Seegers, H.C.; Hood, V.C.; Kidd, B.L.; Cruwys, S.C.; Walsh, D.A. Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J. Pharmacol. Exp. Ther., 2003, 306, 8-12.
Harrison, S.; Geppetti, P.; Substance, P. Int. J. Biochem. Cell Biol., 2001, 33, 555-576.
Weller, M.; Stevens, A.; Sommer, N.; Melms, A.; Dichgans, J.; Wiethölter, H. Comparative analysis of cytokine patterns in immunological, infectious and oncological neurological disorders. J. Neurol. Sci., 1991, 104, 215-221.
Frei, K.; Piani, D.; Malipiero, U.V.; Van Meir, E.; de Tribolet, N.; Fontana, A. Granulocyte-macrophage colony-stimulating factor GM-CSF production by glioblastoma cells. Despite the presence of inducing signals GM-CSF is not expressed in vivo. J. Immunol., 1992, 148, 3140-3146.
Lieb, K.; Fiebich, B.L.; Berger, M.; Bauer, J.; Schulze-Osthoff, K. The neuropeptide substance P activates transcription factor NFkappa B and kappa B-dependent gene expression in human astrocytoma cells. J. Immunol., 1997, 159, 4952-4958.
Lotz, M.; Vaughan, J.H.; Carson, D.A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science, 1988, 241, 1218-1221.
Ho, W.Z.; Kaufman, D.; Uvaydova, M.; Douglas, S.D. Substance P augments interleukin-10 and tumor necrosis factor-alpha release by human cord blood monocytes and macrophages. J. Neuroimmunol., 1996, 71, 73-80.
Rosso, M.; Muñoz, M.; Berger, M. The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. Sci. World J., 2012, 2012, 381434.
Seckl, M.J.; Higgins, T.; Rozengurt, E. [D-Arg1, D-Trp5,7,9, Leu11] substance P coordinately and reversibly inhibits bombesin- and vasopressin-induced signal transduction pathways in Swiss 3T3 cells. J. Biol. Chem., 1996, 271, 29453-29460.
Seckl, M.J.; Higgins, T.; Widmer, F.; Rozengurt, E. [D-Arg1, DTrp5,7,9, Leu11] substance P: A novel potent inhibitor of signal transduction and growth in vitro and in vivo in small cell lung cancer cells. Cancer Res., 1997, 57, 51-54.
Guha, S.; Eibl, G.; Kisfalvi, K.; Fan, R.S.; Burdick, M.; Reber, H.; Hines, O.J.; Strieter, R.; Rozengurt, E. Broad-spectrum G protein coupled receptor antagonist [D-Arg1, D-Trp5,7,9, Leu11] SP: A dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res., 2005, 65, 2738-2745.
Hodkinson, P.S.; Mackinnon, A.; Sethi, T. Targeting growth factors in lung cancer. Chest, 2008, 133, 1209-1216.
Muñoz, M.; Recio, S.; Rosso, M.; Redondo, M.; Coveñas, R. The antitumour action of [DArg1, D-Phe5, D-Trp7,9, Leu11] substance P against small cell- and non-small-cell lung cancer cells is due to the pharmacological profile of its tachykinin receptor antagonist. J. Physiol. Pharmacol., 2015, 66, 421-426.
Muñoz, M.; Coveñas, R. Safety of Neurokinin-1 receptor antagonists. Expert Opin. Drug Saf., 2013, 12, 673-685.
Kramer, M.S.; Cutler, N.; Feighner, J.; Shrivastava, R.; Carman, J.; Sramek, J.J.; Reines, S.A.; Liu, G.; Snavely, D.; Wyatt-Knowles, E.; Hale, J.J.; Mills, S.G.; MacCoss, M.; Swain, C.J.; Harrison, T.; Hill, R.G.; Hefti, F.; Scolnick, E.M.; Cascieri, M.A.; Chicchi, G.G.; Sadowski, S.; Williams, A.R.; Hewson, L.; Smith, D.; Carlson, E.J.; Hargreaves, R.J.; Rupniak, N.M. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science, 1998, 281, 1640-1645.
Harford-Wright, E.; Lewis, K.M.; Ghabriel, M.N.; Vink, R. Treatment with the NK1 antagonist Emend reduces blood brain barrier dysfunction and edema formation in an experimental model of brain tumors. PLoS One, 2014, 9, e97002.
Medrano, S.; Gruenstein, E.; Dimlich, R.V. Substance P receptors on human astrocytoma cells are linked to glycogen breakdown. Neurosci. Lett., 1994, 167, 14-18.
Palma, C.; Bigioni, M.; Irrissuto, C.; Nardelli, F.; Maggi, C.A.; Manzini, S. Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft. Br. J. Cancer, 2000, 82, 480-487.
Akazawa, T.; Kwatra, S.G.; Goldsmith, L.E.; Richardson, M.D.; Cox, E.A.; Sampson, J.H.; Kwatra, M.M. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J. Neurochem., 2009, 109, 1079-1086.
Li, X.; Ma, G.; Ma, Q.; Li, W.; Liu, J.; Han, L.; Duan, W.; Xu, Q.; Liu, H.; Wang, Z.; Sun, Q.; Wang, F.; Wu, E. Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol. Cancer Res., 2013, 11, 294-302.
Berger, M.; Neth, O.; Ilmer, M.; Garnier, A.; Salinas-Martín, M.V.; de Agustín Asencio, J.C.; von Schweinitz, D.; Kappler, R.; Muñoz, M. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be inhibited by aprepitant in vitro and in vivo. J. Hepatol., 2014, 60, 985-994.
Bang, R.; Sass, G.; Kiemer, A.K.; Vollmar, A.M.; Neuhuber, W.L.; Tiegs, G. Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. J. Pharmacol. Exp. Ther., 2003, 305, 31-39.
Svensson, C.I.; Lucas, K.K.; Hua, X.Y.; Powell, H.C.; Dennis, E.A.; Yaksh, T.L. Spinal phospholipase A2 in inflammatory hyperalgesia: role of the small, secretory phospholipase A2. Neuroscience, 2005, 133, 543-553.
Kast, R.E.; Boockvar, J.A.; Brüning, A.; Cappello, F.; Chang, W.W.; Cvek, B.; Dou, Q.P.; Dueñas-González, A.; Efferth, T.; Focosi, D.; Ghaffari, S.H.; Karpel-Massler, G.; Ketola, K.; Khoshnevisan, A.; Keizman, D.; Magné, N.; Marosi, C.; McDonald, K.; Muñoz, M.; Paranjpe, A.; Pourgholami, M.H.; Sardi, I.; Sella, A.; Srivenugopal, K.S.; Tuccori, M.; Wang, W.; Wirtz, C.R.; Halatsch, M.E. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the international initiative for accelerated improvement of glioblastoma care. Oncotarget, 2013, 4, 502-530.
Kast, R.E.; Ramiri, S.; Lladó, S.; Toro, S.; Coveñas, R.; Muñoz, M. Antitumor action of temozolomide, ritonavir and aprepitant agaisnt human glioma cells. J. Neurooncol., 2016, 126, 425-431.
Thorne, A.H.; Zanca, C.; Furnari, F. Epidermal growth factor receptor targeting and challenges in glioblastoma. Neuro-oncol., 2016, 18, 914-918.
Mitsuhashi, M.; Ohashi, Y.; Schichijo, S.; Christian, C.; Sudduth-Klinger, J.; Harrowe, G.; Payan, D.G. Multiple intracellular signalling pathways of the neuropeptide SP receptor. J. Neurosci. Res., 1992, 32, 437-443.
Castagliuolo, I.; Valenick, L.; Liu, J.; Pothoulakis, C. Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells. J. Biol. Chem., 2000, 275, 26545-26550.
Wang, Z. Transactivation of epidermal growth factor receptor by G protein-coupled receptors: Recent progress, challenges and future research. Int. J. Mol. Sci., 2016, 17, 95.
Cattaneo, F.; Guerra, G.; Parisi, M.; de Marinis, M.; Tafuri, D.; Cinelli, M.; Ammendola, R. Cell-surface receptors transactivation mediated by G protein-coupled receptors. Int. J. Mol. Sci., 2014, 15, 19700-19728.
Luttrell, D.K.; Luttrell, L.M. Not so strange bedfellows: G-proteing-coupled receptors and Src family kinases. Oncogene, 2004, 23, 7969-7978.
Yamaguchi, K.; Richardson, M.D.; Bigner, D.D.; Kwatra, M.M. Signal transduction through substance P receptor in human glioblastoma cells: Roles for Src and PKCδ. Cancer Chemother. Pharmacol., 2005, 56, 585-593.
García-Recio, S.; Pastor-Arroyo, E.M.; Marín-Aguilera, M.; Almendro, V.; Gascón, P. The transmodulation of HER2 and EGFR by substance P in breast cancer cells requires c-Src and metalloproteinase activation. PLoS One, 2015, 10, e0129661.
Li, X.; Wu, C.; Chen, N.; Gu, H.; Yen, A.; Cao, L.; Wang, E.; Wang, L. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget, 2016, 7, 33440-33450.
Nakajima, Y.; Tsuchida, K.; Negishi, M.; Ito, S.; Nakanishi, S. Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cAMP cascades in transfected Chinese hamster ovary cells. J. Biol. Chem., 1992, 267, 2437-2442.
Takeda, Y.; Blount, P.; Sachais, B.S.; Hershey, A.D.; Raddatz, R.; Krause, J.E. Ligand binding kinetics of substance P and neurokinin receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1, 4, 5-triphosphate and cyclic AMP second messenger responses. J. Neurochem., 1992, 59, 740-745.
Vredenburgh, J.J.; Desjardins, A.; Herndon, J.E., II; Marcello, J.; Reardon, D.A.; Quinn, J.A.; Rich, J.N.; Sathornsumetee, S.; Gururangan, S.; Sampson, J.; Wagner, M.; Bailey, L.; Bigner, D.D.; Friedman, A.H.; Friedman, H.S. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol., 2007, 25, 4722-4729.
Friedman, H.S.; Prados, M.D.; Wen, P.Y.; Mikkelsen, T.; Schiff, D.; Abrey, L.E.; Yung, W.K.A.; Paleologos, N.; Nicholas, M.K.; Jensen, R.; Vredenburgh, J.; Huang, J.; Zheng, M.; Cloughesy, T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol., 2009, 27, 4733-4740.
Moriya, S.; Ohba, S.; Adachi, K.; Nishiyama, Y.; Hayashi, T.; Nagahisa, S.; Kaito, T.; Nakae, S.; Hirose, Y. A retrospective study of bevacizumab for treatment of brainstem glioma with malignant features. J. Clin. Neurosci., 2018, 47, 228-233.
Tamura, R.; Tanaka, T.; Miyake, K.; Yoshida, K.; Sasaki, H. Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol., 2017, 34, 62-77.
Yonezawa, H.; Hirano, H.; Uchida, H.; Habu, M.; Hanaya, R.; Oyoshi, T.; Sadamura, Y.; Hanada, T.; Tokimura, H.; Moinuddin, F.; Arita, K. Efficacy of bevacizumab therapy for unresectable malignant glioma: A retrospective analysis. Mol. Clin. Oncol., 2017, 6, 105-110.
Tabouret, E.; Tchoghandjian, A.; Denicolai, E.; Delfino, C.; Metellus, P.; Graillon, T.; Boucard, C.; Nanni, I.; Padovani, L.; Ouafik, L.; Figarella-Branger, D.; Chinot, O. Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway. Oncotarget, 2015, 6, 11664-11675.
Theoharides, T.C.; Zhang, B.; Kempuraj, D.; Tagen, M.; Vasiadi, M.; Angelidou, A.; Alysandratos, K.D.; Kalogeromitros, D.; Asadi, S.; Stavrianeas, N.; Peterson, E.; Leeman, S.; Conti, P. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc. Natl. Acad. Sci. USA, 2010, 107, 4448-4453.
Yamaguchi, K.; Kumakura, S.; Murakami, T.; Someya, A.; Inada, E.; Nagaoka, I. Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells. Int. J. Mol. Med., 2017, 39, 687-692.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [92 - 100]
Pages: 9
DOI: 10.2174/1871520618666180420165401
Price: $58

Article Metrics

PDF: 26