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Review Article

Neurokinin-1 Receptor Antagonists as Anticancer Drugs

Author(s): Miguel Muñoz* and Rafael Coveñas

Volume 16, Issue 10, 2019

Page: [1110 - 1129] Pages: 20

DOI: 10.2174/1570180816666190221091955

Price: $65

Abstract

Background: Human tumor cells lines and tumor samples overexpress the neurokinin-1 receptor (NK-1R). Substance P (SP), after binding to NK-1Rs, induces tumor cell proliferation, an antiapoptotic effect and promotes angiogenesis and the migration of cancer cells for invasion and metastasis.

Methods: In contrast, NK-1R antagonists block the previous pathophysiological actions mediated by SP. These antagonists promote the death of tumor cells by apoptosis. Peptide and non-peptide NK-1R antagonists have been reported.

Results: Peptide NK-1R antagonists show chemical modifications of the SP molecule (L-amino acids being replaced by D-amino acids), whereas non-peptide NK-1R antagonists include numerous compounds with different chemical compositions while showing similar stereochemical features (affinity for the NK- 1R). Currently, there are more than 300 NK-1R antagonists.

Conclusion: In combination therapy with classic cytostatics, NK-1R antagonists have additive or synergic effects and minimize the side-effects of cytostatics. The effect of NK-1R antagonists as broad-spectrum anticancer drugs is reviewed and the use of these antagonists for the treatment of cancer is suggested.

Keywords: Angiogenesis, apoptosis, metastasis, NK-1 receptor, substance P, tumor cell.

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[1]
World Health Organization. 2018.http://www.who.int/news-room/fact-sheets/detail/cancer
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[3]
Morgan, G.; Ward, R.; Barton, M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin. Oncol. (R. Coll. Radiol.), 2004, 16(8), 549-560.
[http://dx.doi.org/10.1016/j.clon.2004.06.007] [PMID: 15630849]
[4]
Wang, S.; Tang, J.; Sun, T.; Zheng, X.; Li, J.; Sun, H.; Zhou, X.; Zhou, C.; Zhang, H.; Cheng, Z.; Ma, H.; Sun, H. Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages. Sci. Rep., 2017, 7(1), 1339.
[http://dx.doi.org/10.1038/s41598-017-01571-0] [PMID: 28465554]
[5]
Sun, H.; Ma, H.; Hong, G.; Sun, H.; Wang, J. Survival improvement in patients with pancreatic cancer by decade: a period analysis of the SEER database, 1981-2010. Sci. Rep., 2014, 4, 6747.
[http://dx.doi.org/10.1038/srep06747] [PMID: 25339498]
[6]
McLendon, R.E.; Halperin, E.C. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer, 2003, 98(8), 1745-1748.
[http://dx.doi.org/10.1002/cncr.11666] [PMID: 14534892]
[7]
Muñoz, M.; Rosso, M.; Aguilar, F.J.; González-Moles, M.A.; Redondo, M.; Esteban, F. NK-1 receptor antagonists induce apoptosis and counteract substance P-related mitogenesis in human laryngeal cancer cell line HEp-2. Invest. New Drugs, 2008, 26(2), 111-118.
[http://dx.doi.org/10.1007/s10637-007-9087-y] [PMID: 17906845]
[8]
Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides, 2013, 48, 1-9.
[http://dx.doi.org/10.1016/j.peptides.2013.07.024] [PMID: 23933301]
[9]
Muñoz, M.; Rosso, M.; Robles-Frías, M.J.; Salinas-Martín, M.V.; Rosso, R.; González-Ortega, A.; Coveñas, R. The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. Lab. Invest., 2010, 90(8), 1259-1269.
[http://dx.doi.org/10.1038/labinvest.2010.92] [PMID: 20458280]
[10]
Muñoz, M.; Berger, M.; Rosso, M.; González-Ortega, A.; Carranza, A.; Coveñas, R. Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts. Int. J. Oncol., 2014, 44(1), 137-146.
[http://dx.doi.org/10.3892/ijo.2013.2164] [PMID: 24190675]
[11]
Muñoz, M.; Recio, S.; Rosso, M.; Redondo, M.; Coveñas, R. The antiproliferative action of [D-Arg(1), D-Phe(5), D-Trp(7,9), LEU(11)] substance P analogue antagonist against small-cell- and non-small-cell lung cancer cells could be due to the pharmacological profile of its tachykinin receptor antagonist. J. Physiol. Pharmacol., 2015, 66(3), 421-426.
[PMID: 26084224]
[12]
Muñoz, M.; González-Ortega, A.; Salinas-Martín, M.V.; Carranza, A.; García-Recio, S.; Almendro, V.; Coveñas, R. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int. J. Oncol., 2014, 45(4), 1658-1672.
[http://dx.doi.org/10.3892/ijo.2014.2565] [PMID: 25175857]
[13]
Muñoz, M.; González-Ortega, A.; Rosso, M.; Robles-Frías, M.J.; Carranza, A.; Salinas-Martín, M.V.; Coveñas, R. The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. Peptides, 2012, 38(2), 318-325.
[http://dx.doi.org/10.1016/j.peptides.2012.09.024] [PMID: 23026680]
[14]
Muñoz, M.; Rosso, M.; Coveñas, R. The NK-1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on human pancreatic cancer cell lines. Lett. Drug Des. Discov., 2006, 3, 323-329.
[http://dx.doi.org/10.2174/157018006777574168]
[15]
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(2), 441-463.
[http://dx.doi.org/10.1007/s12038-015-9530-8] [PMID: 25963269]
[16]
Muñoz, M.; Rosso, M.; Coveñas, R.; Montero, I.; González-Moles, M.A.; Robles, M.J. Neurokinin-1 receptors located in human retinoblastoma cell lines: antitumor action of its antagonist, L-732,138. Invest. Ophthalmol. Vis. Sci., 2007, 48(6), 2775-2781.
[http://dx.doi.org/10.1167/iovs.05-1591] [PMID: 17525212]
[17]
Muñoz, M.; González-Ortega, A.; Coveñas, R. The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines. Invest. New Drugs, 2012, 30(2), 529-540.
[http://dx.doi.org/10.1007/s10637-010-9594-0] [PMID: 21120581]
[18]
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(1), 31-39.
[http://dx.doi.org/10.1124/jpet.102.043539] [PMID: 12649350]
[19]
Rupniak, N.M.; Carlson, E.; Boyce, S.; Webb, J.K.; Hill, R.G. Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils. Pain, 1996, 67(1), 189-195.
[http://dx.doi.org/10.1016/0304-3959(96)03109-0] [PMID: 8895247]
[20]
Tattersall, F.D.; Rycroft, W.; Cumberbatch, M.; Mason, G.; Tye, S.; Williamson, D.J.; Hale, J.J.; Mills, S.G.; Finke, P.E.; MacCoss, M.; Sadowski, S.; Ber, E.; Cascieri, M.; Hill, R.G.; MacIntyre, D.E.; Hargreaves, R.J. The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets. Neuropharmacology, 2000, 39(4), 652-663.
[http://dx.doi.org/10.1016/S0028-3908(99)00172-0] [PMID: 10728886]
[21]
Yu, J.; Cadet, J.L.; Angulo, J.A. Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. J. Neurochem., 2002, 83(3), 613-622.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01155.x] [PMID: 12390523]
[22]
Almeida, T.A.; Rojo, J.; Nieto, P.M.; Pinto, F.M.; Hernández, M.; Martín, J.D.; Candenas, M.L. Tachykinins and tachykinin receptors: structure and activity relationships. Curr. Med. Chem., 2004, 11(15), 2045-2081.
[http://dx.doi.org/10.2174/0929867043364748] [PMID: 15279567]
[23]
Woll, P.J.; Rozengurt, E. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro. Proc. Natl. Acad. Sci. USA, 1988, 85(6), 1859-1863.
[http://dx.doi.org/10.1073/pnas.85.6.1859] [PMID: 2450349]
[24]
Everard, M.J.; Macaulay, V.M.; Miller, J.L.; Smith, I.E. In vitro effects of substance P analogue [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P on human tumour and normal cell growth. Br. J. Cancer, 1992, 65(3), 388-392.
[http://dx.doi.org/10.1038/bjc.1992.78] [PMID: 1373071]
[25]
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(7), 2738-2745.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3197] [PMID: 15805273]
[26]
Snider, R.M.; Constantine, J.W.; Lowe, J.A., III; Longo, K.P.; Lebel, W.S.; Woody, H.A.; Drozda, S.E.; Desai, M.C.; Vinick, F.J.; Spencer, R.W. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science, 1991, 251(4992), 435-437.
[http://dx.doi.org/10.1126/science.1703323] [PMID: 1703323]
[27]
Maggi, C.A.; Patacchini, R.; Rovero, P.; Giachetti, A. Tachykinin receptors and tachykinin receptor antagonists. J. Auton. Pharmacol., 1993, 13(1), 23-93.
[http://dx.doi.org/10.1111/j.1474-8673.1993.tb00396.x] [PMID: 8382703]
[28]
Regoli, D.; Boudon, A.; Fauchére, J.L. Receptors and antagonists for substance P and related peptides. Pharmacol. Rev., 1994, 46(4), 551-599.
[PMID: 7534932]
[29]
Giardina, G.A.M.; Gagliardi, S.; Martinelli, M. Antagonists at the neurokinin receptors--recent patent literature. IDrugs, 2003, 6(8), 758-772.
[PMID: 12917772]
[30]
Quartara, L.; Maggi, C.A. The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides, 1997, 31(6), 537-563.
[http://dx.doi.org/10.1016/S0143-4179(97)90001-9] [PMID: 9574822]
[31]
Muñoz, M.; Coveñas, R. Safety of neurokinin-1 receptor antagonists. Expert Opin. Drug Saf., 2013, 12(5), 673-685.
[http://dx.doi.org/10.1517/14740338.2013.804059] [PMID: 23706125]
[32]
Hökfelt, T.; Pernow, B.; Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med., 2001, 249(1), 27-40.
[http://dx.doi.org/10.1046/j.0954-6820.2000.00773.x] [PMID: 11168782]
[33]
Bigioni, M.; Benzo, A.; Irrissuto, C.; Maggi, C.A.; Goso, C. Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231. Anticancer Drugs, 2005, 16(10), 1083-1089.
[http://dx.doi.org/10.1097/00001813-200511000-00007] [PMID: 16222150]
[34]
Huang, W.Q.; Wang, J.G.; Chen, L.; Wei, H.J.; Chen, H., Sr -140, 333 counteracts NK-1 mediated cell proliferation in hu-man breast cancer cell line T47D. J. Exp. Clin. Cancer Res., 2010, 24, 29-55.
[35]
Singh, D.; Joshi, D.D.; Hameed, M.; Qian, J.; Gascón, P.; Maloof, P.B.; Mosenthal, A.; Rameshwar, P. Increased ex-pression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow me-tastasis. Proc. Natl. Acad. Sci. USA, 2000, 97, 1388-1393.
[http://dx.doi.org/10.1073/pnas.97.1.388]
[36]
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(6)e0129661
[http://dx.doi.org/10.1371/journal.pone.0129661] [PMID: 26114632]
[37]
Wang, J.G.; Yu, J.; Hu, J.L.; Yang, W.L.; Ren, H.; Ding, D.; Zhang, L.; Liu, X.P. Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer. Cell. Signal., 2015, 27(7), 1315-1324.
[http://dx.doi.org/10.1016/j.cellsig.2015.03.015] [PMID: 25817575]
[38]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[39]
Spira, A.; Halmos, B.; Powell, C.A. Update in lung cancer 2014. Am. J. Respir. Crit. Care Med., 2015, 192(3), 283-294.
[http://dx.doi.org/10.1164/rccm.201504-0756UP] [PMID: 26230235]
[40]
Ferlay, J.; Steliarova-Foucher, E.; Lortet-Tieulent, J.; Rosso, S.; Coebergh, J.W.; Comber, H.; Forman, D.; Bray, F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer, 2013, 49(6), 1374-1403.
[http://dx.doi.org/10.1016/j.ejca.2012.12.027] [PMID: 23485231]
[41]
Hodkinson, P.S.; Mackinnon, A.; Sethi, T. Targeting growth factors in lung cancer. Chest, 2008, 133(5), 1209-1216.
[http://dx.doi.org/10.1378/chest.07-2680] [PMID: 18460519]
[42]
Woll, P.J.; Rozengurt, E. A neuropeptide antagonist that inhibits the growth of small cell lung cancer in vitro. Cancer Res., 1990, 50(13), 3968-3973.
[PMID: 1693879]
[43]
Waters, C.M.; MacKinnon, A.C.; Cummings, J.; Tufail-Hanif, U.; Jodrell, D.; Haslett, C.; Sethi, T. Increased gastrin-releasing peptide (GRP) receptor expression in tumour cells confers sensitivity to [Arg6,D-Trp7,9,NmePhe8]-substance P (6-11)-induced growth inhibition. Br. J. Cancer, 2003, 88(11), 1808-1816.
[http://dx.doi.org/10.1038/sj.bjc.6600957] [PMID: 12771999]
[44]
Clive, S.; Webb, D.J.; MacLellan, A.; Young, A.; Byrne, B.; Robson, L.; Smyth, J.F.; Jodrell, D.I. Forearm blood flow and local responses to peptide vasodilators: a novel pharmacodynamic measure in the phase I trial of antagonist G, a neuropeptide growth factor antagonist. Clin. Cancer Res., 2001, 7(10), 3071-3078.
[PMID: 11595697]
[45]
Jemal, A.; Center, M.M.; DeSantis, C.; Ward, E.M. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol. Biomarkers Prev., 2010, 19(8), 1893-1907.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0437] [PMID: 20647400]
[46]
Muñoz, M.; Rosso, M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest. New Drugs, 2010, 28(2), 187-193.
[http://dx.doi.org/10.1007/s10637-009-9218-8] [PMID: 19148578]
[47]
Esteban, F.; González-Moles, M.A.; Castro, D. Martin-Jaen, Mdel.M.; Redondo, M.; Ruiz-Avila, I.; Muñoz, M. Expression of substance P and neurokinin-1-receptor in laryngeal cancer: linking chronic inflammation to cancer promotion and progression. Histopathology, 2009, 54(2), 258-260.
[http://dx.doi.org/10.1111/j.1365-2559.2008.03193.x] [PMID: 19207952]
[48]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin., 2013, 63(1), 11-30.
[http://dx.doi.org/10.3322/caac.21166] [PMID: 23335087]
[49]
Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J.L. Pancreatic cancer. Lancet, 2004, 363(9414), 1049-1057.
[http://dx.doi.org/10.1016/S0140-6736(04)15841-8] [PMID: 15051286]
[50]
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 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab. Invest., 2003, 83(5), 731-742.
[http://dx.doi.org/10.1097/01.LAB.0000067499.57309.F6] [PMID: 12746482]
[51]
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(3), 294-302.
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0609] [PMID: 23345604]
[52]
Burt, R.W. Colon cancer screening. Gastroenterology, 2000, 119(3), 837-853.
[http://dx.doi.org/10.1053/gast.2000.16508] [PMID: 10982778]
[53]
Rosso, M.; Robles-Frías, M.J.; Coveñas, R.; Salinas-Martín, M.V.; Muñoz, M. The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines. Tumour Biol., 2008, 29(4), 245-254.
[http://dx.doi.org/10.1159/000152942] [PMID: 18781096]
[54]
Gillespie, E.; Leeman, S.E.; Watts, L.A.; Coukos, J.A.; O’Brien, M.J.; Cerda, S.R.; Farraye, F.A.; Stucchi, A.F.; Becker, J.M. Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer. Proc. Natl. Acad. Sci. USA, 2011, 108(42), 17420-17425.
[http://dx.doi.org/10.1073/pnas.1114275108] [PMID: 21969570]
[55]
Isidro, R.A.; Cruz, M.L.; Isidro, A.A.; Báez, A.; Arroyo, A.; González-Marqués, W.A.; González-Keelan, C.; Torres, E.A.; Appleyard, C.B. Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia. World J. Gastroenterol., 2015, 21(6), 1749-1758.
[http://dx.doi.org/10.3748/wjg.v21.i6.1749] [PMID: 25684939]
[56]
Niu, X.L.; Hou, J.F.; Li, J.X. The NK1 receptor antagonist NKP608 inhibits proliferation of human colorectal cancer cells via Wnt signaling pathway. Biol. Res., 2018, 51(1), 14.
[http://dx.doi.org/10.1186/s40659-018-0163-x] [PMID: 29843798]
[57]
Muñoz, M.; Rosso, M.; González, 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(9), 1643-1648.
[http://dx.doi.org/10.1016/j.peptides.2010.06.002] [PMID: 20542069]
[58]
Karpeh, M.S.; Kelsen, D.P.; Tepper, J.E. In: Cancer: Principles and Practice on Oncology; DeVita, Hellman and Rosenberg, Eds.; Lippincott Williams & Wilkins: Philadelphia, 2001; pp. 1092-1126. [59] Muñoz, M.; Rosso, M.; Carranza, A.; Coveñas, R. Increased nuclear localization of substance P in human gastric tumor cells. Acta Histochem; , 2001. 119, pp. 337-342.
[59]
Muñoz, M.; Rosso, M.; Carranza, A.; Coveñas, R. Increased nuclear localization of substance P in human gastric tumor cells. Acta Histochem., 2017, 119(3), 337-342.
[http://dx.doi.org/10.1016/j.acthis.2017.03.003] [PMID: 28325510]
[60]
Feng, F.; Yang, J.; Tong, L.; Yuan, S.; Tian, Y.; Hong, L.; Wang, W.; Zhang, H. Substance P immunoreactive nerve fibres are related to gastric cancer differentiation status and could promote proliferation and migration of gastric cancer cells. Cell Biol. Int., 2011, 35(6), 623-629.
[http://dx.doi.org/10.1042/CBI20100229] [PMID: 21091434]
[61]
Lazaridis, K.N.; Gores, G.J. Cholangiocarcinoma. Gastroenterology, 2005, 128(6), 1655-1667.
[http://dx.doi.org/10.1053/j.gastro.2005.03.040] [PMID: 15887157]
[62]
Meng, F.; DeMorrow, S.; Venter, J.; Frampton, G.; Han, Y.; Francis, H.; Standeford, H.; Avila, S.; McDaniel, K.; McMillin, M.; Afroze, S.; Guerrier, M.; Quezada, M.; Ray, D.; Kennedy, L.; Hargrove, L.; Glaser, S.; Alpini, G. Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth. Am. J. Physiol. Gastrointest. Liver Physiol., 2014, 306(9), G759-G768.
[http://dx.doi.org/10.1152/ajpgi.00018.2014] [PMID: 24603459]
[63]
Dong, J.; Feng, F.; Xu, G.; Zhang, H.; Hong, L.; Yang, J. Elevated SP/NK-1R in esophageal carcinoma promotes esophageal carcinoma cell proliferation and migration. Gene, 2015, 560(2), 205-210.
[http://dx.doi.org/10.1016/j.gene.2015.02.002] [PMID: 25659767]
[64]
Morice, P.; Leary, A.; Creutzberg, C.; Abu-Rustum, N.; Darai, E. Endometrial cancer. Lancet, 2016, 387(10023), 1094-1108.
[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]
[65]
Ma, J.; Yuan, S.; Cheng, J.; Kang, S.; Zhao, W.; Zhang, J. Substance P promotes the progression of endometrial adeno-carcinoma. Int. J. Gynecol. Cancer, 2016, 26(5), 845-850.
[http://dx.doi.org/10.1097/IGC.0000000000000683] [PMID: 27051050]
[66]
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), 1-10.
[http://dx.doi.org/10.3171/jns.1998.88.1.0001] [PMID: 9420066]
[67]
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fish-er, 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.; Eisen-hauer, E.; Mirimanoff, R.O. European Organisation for Re-search and Treatment of Cancer Brain Tumor and Radiothera-py Groups. National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant te-mozolomide for glioblastoma. N. Engl. J. Med., 2005, 352, 987-996.
[http://dx.doi.org/10.1056/NEJMoa043330] [PMID: 15758009]
[68]
Alifieris, C.; Trafalis, D.T. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol. Ther., 2015, 152, 63-82.
[http://dx.doi.org/10.1016/j.pharmthera.2015.05.005] [PMID: 25944528]
[69]
Thorne, A.H.; Zanca, C.; Furnari, F. Epidermal growth factor receptor targeting and challenges in glioblastoma. Neuro-oncol., 2016, 18(7), 914-918.
[http://dx.doi.org/10.1093/neuonc/nov319] [PMID: 26755074]
[70]
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(6), 786-792.
[http://dx.doi.org/10.1002/ijc.2910610608] [PMID: 7790112]
[71]
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(5), 1813-1820.
[http://dx.doi.org/10.1046/j.1471-4159.1996.67051813.x] [PMID: 8863485]
[72]
Palma, C.; Nardelli, F.; Manzini, S.; Maggi, C.A. Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors. Br. J. Cancer, 1999, 79(2), 236-243.
[http://dx.doi.org/10.1038/sj.bjc.6690039] [PMID: 9888463]
[73]
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(1-2), 48-56.
[http://dx.doi.org/10.1016/j.jneuroim.2005.03.016] [PMID: 15913794]
[74]
Muñoz, M.; Rosso, M.; Pérez, A.; Coveñas, R.; Rosso, R.; Zamarriego, C.; Piruat, J.I. The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines. Neuropeptides, 2005, 39(4), 427-432.
[http://dx.doi.org/10.1016/j.npep.2005.03.004] [PMID: 15939468]
[75]
Fowler, C.J.; Brännström, G. Substance P enhances forskolin-stimulated cyclic AMP production in human UC11MG astrocytoma cells. Methods Find. Exp. Clin. Pharmacol., 1994, 16(1), 21-28.
[PMID: 7513037]
[76]
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(4), 1079-1086.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06032.x] [PMID: 19519779]
[77]
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(2), 480-487.
[http://dx.doi.org/10.1054/bjoc.1999.0946] [PMID: 10646908]
[78]
American Cancer Society. Cancer Facts and Figs. 2007-2008; American Cancer Society: Atlanta, 2007.
[79]
Khare, V.K.; Albino, A.P.; Reed, J.A. The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions. J. Cutan. Pathol., 1998, 25(1), 2-10.
[http://dx.doi.org/10.1111/j.1600-0560.1998.tb01682.x] [PMID: 9508337]
[80]
Muñoz, M.; Pérez, A.; Rosso, M.; Zamarriego, C.; Rosso, R. Antitumoral action of the neurokinin-1 receptor antagonist L-733 060 on human melanoma cell lines. Melanoma Res., 2004, 14(3), 183-188.
[http://dx.doi.org/10.1097/01.cmr.0000129376.22141.a3] [PMID: 15179186]
[81]
Muñoz, M.; Rosso, M.; González-Ortega, A.; Coveñas, R. The NK-1 receptor antagonist L-732,138 induces apoptosis and counteracts substance P-related mitogenesis in human mela-noma cell lines. Cancers (Basel), 2010, 2(2), 611-623.
[http://dx.doi.org/10.3390/cancers2020611] [PMID: 24281084]
[82]
González-Ortega, A.; Sánchez-Vaderrábanos, E.; Ramiro-Fuentes, S.; Salinas-Martín, M.V.; Carranza, A.; Coveñas, R.; Muñoz, M. Uveal melanoma expresses NK-1 receptors and cyclosporin A induces apoptosis in human melanoma cell lines overexpressing the NK-1 receptor. Peptides, 2014, 55, 1-12.
[http://dx.doi.org/10.1016/j.peptides.2014.01.030] [PMID: 24548567]
[83]
Perentes, E.; Herbort, C.P.; Rubinstein, L.J.; Herman, M.M.; Uffer, S.; Donoso, L.A.; Collins, V.P. Immunohistochemical characterization of human retinoblastomas in situ with multiple markers. Am. J. Ophthalmol., 1987, 103(5), 647-658.
[http://dx.doi.org/10.1016/S0002-9394(14)74324-7] [PMID: 3555097]
[84]
Broaddus, E.; Topham, A.; Singh, A.D. Incidence of retinoblastoma in the USA: 1975-2004. Br. J. Ophthalmol., 2009, 93(1), 21-23.
[http://dx.doi.org/10.1136/bjo.2008.138750] [PMID: 18621794]
[85]
Shields, C.L.; Shields, J.A. Diagnosis and management of retinoblastoma. Cancer Contr., 2004, 11(5), 317-327.
[http://dx.doi.org/10.1177/107327480401100506] [PMID: 15377991]
[86]
Muñoz, M.; Rosso, M.; Pérez, A.; Coveñas, R.; Rosso, R.; Zamarriego, C.; Soult, J.A.; Montero, I. Antitumoral action of the neurokinin-1-receptor antagonist L-733,060 and mitogenic action of substance P on human retinoblastoma cell lines. Invest. Ophthalmol. Vis. Sci., 2005, 46(7), 2567-2570.
[http://dx.doi.org/10.1167/iovs.04-1530] [PMID: 15980249]
[87]
Henssen, A.G.; Odersky, A.; Szymansky, A.; Seiler, M.; Althoff, K.; Beckers, A.; Speleman, F.; Schäfers, S.; De Preter, K.; Astrahanseff, K.; Struck, J.; Schramm, A.; Eggert, A.; Bergmann, A.; Schulte, J.H. Targeting tachykinin receptors in neuroblastoma. Oncotarget, 2017, 8(1), 430-443.
[http://dx.doi.org/10.18632/oncotarget.13440] [PMID: 27888795]
[88]
Muñoz, M.; Rosso, M.; Coveñas, R. In: Focus on Neuroblastoma Research; Fernandes, Ed.; Nova Science Publishers: New York,; , 2007, pp. 31-56.
[89]
Nowicki, M.; Miśkowiak, B. Comparison of the cell immunophenotype of metastatic and primary foci in stage IV-S neuroblastoma. Folia Histochem. Cytobiol., 2002, 40(3), 297-303.
[PMID: 12219840]
[90]
Pohl, A.; Kappler, R.; Mühling, J. V.O.N. Schweinitz, D.; Berger, M. Expression of truncated neurokinin-1 receptor in child-hood neuroblastoma is independent of tumor biology and stage. Anticancer Res., 2017, 37(11), 6079-6085.
[PMID: 29061788]
[91]
Wittig, J.C.; Bickels, J.; Priebat, D.; Jelinek, J.; Kellar-Graney, K.; Shmookler, B.; Malawer, M.M. Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am. Fam. Physician, 2002, 65(6), 1123-1132.
[PMID: 11925089]
[92]
Ritter, J.; Bielack, S.S. Osteosarcoma. Ann. Oncol., 2010, 21(Suppl. 7), vii320-vii325.
[http://dx.doi.org/10.1093/annonc/mdq276] [PMID: 20943636]
[93]
von Schweinitz, D. Management of liver tumors in childhood. Semin. Pediatr. Surg., 2006, 15(1), 17-24.
[http://dx.doi.org/10.1053/j.sempedsurg.2005.11.004] [PMID: 16458842]
[94]
von Schweinitz, D. Hepatoblastoma: recent developments in research and treatment. Semin. Pediatr. Surg., 2012, 21(1), 21-30.
[http://dx.doi.org/10.1053/j.sempedsurg.2011.10.011] [PMID: 22248967]
[95]
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 growth inhibited by aprepitant in vitro and in vivo. J. Hepatol., 2014, 60(5), 985-994.
[http://dx.doi.org/10.1016/j.jhep.2013.12.024] [PMID: 24412605]
[96]
Ries, L.A.; Kosary, C.L.; Hankey, B.F.; Miller, B.A.; Clegg, L.; Edwards, B.K. SEER cancer statistics review, 1973.1996; National Cancer Institute: Bethesda, 1999.
[97]
Pui, C.H.; Relling, M.V.; Downing, J.R. Acute lymphoblastic leukemia. N. Engl. J. Med., 2004, 350(15), 1535-1548.
[http://dx.doi.org/10.1056/NEJMra023001] [PMID: 15071128]
[98]
Payan, D.G.; McGillis, J.P.; Organist, M.L. Binding characteristics and affinity labeling of protein constituents of the human IM-9 lymphoblast receptor for substance P. J. Biol. Chem., 1986, 261(30), 14321-14329.
[PMID: 2429956]
[99]
Nowicki, M.; Miśkowiak, B.; Ostalska-Nowicka, D. Detection of substance P and its mRNA in human blast cells in childhood lymphoblastic leukaemia using immunocytochemistry and in situ hybridisation. Folia Histochem. Cytobiol., 2003, 41(1), 33-36.
[PMID: 12705477]
[100]
Nowicki, M.; Miśkowiak, B. Substance P-a potent risk factor in childhood lymphoblastic leukaemia. Leukemia, 2003, 17(6), 1096-1099.
[http://dx.doi.org/10.1038/sj.leu.2402920] [PMID: 12764374]
[101]
Bayati, S.; Bashash, D.; Ahmadian, S.; Safaroghli-Azar, A.; Alimoghaddam, K.; Ghavamzadeh, A.; Ghaffari, S.H. Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells. Eur. J. Pharmacol., 2016, 791, 274-283.
[http://dx.doi.org/10.1016/j.ejphar.2016.09.006] [PMID: 27609608]
[102]
Deschler, B.; Lübbert, M. Acute myeloid leukemia: epidemiology and etiology. Cancer, 2006, 107(9), 2099-2107.
[http://dx.doi.org/10.1002/cncr.22233] [PMID: 17019734]
[103]
Molinos-Quintana, A.; Trujillo-Hacha, P.; Piruat, J.I. Bejara-no-García, J.A.; García Guerrero, E.; Pérez-Simón, J.A.; Muñoz, M. Human acute myeloid leukemia cells express neu-rokinin-1 receptor, which is involved in the antileukemic ef-fect of neurokinin-1 receptor antagonists. Invest. New Drugs, 2019, 37, 17-26.
[http://dx.doi.org/10.1007/s10637-018-0607-8] [PMID: 29721755]
[104]
Bayati, S.; Razani, E.; Bashash, D.; Safaroghli-Azar, A.; Safa, M.; Ghaffari, S.H. Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant. Anticancer Drugs, 2018, 29(3), 243-252.
[PMID: 29389803]
[105]
Sporn, M.B. The war on cancer. Lancet, 1996, 347(9012), 1377-1381.
[http://dx.doi.org/10.1016/S0140-6736(96)91015-6] [PMID: 8637346]
[106]
Fackler, O.T.; Grosse, R. Cell motility through plasma membrane blebbing. J. Cell Biol., 2008, 181(6), 879-884.
[http://dx.doi.org/10.1083/jcb.200802081] [PMID: 18541702]
[107]
Meshki, J.; Douglas, S.D.; Lai, J.P.; Schwartz, L.; Kilpatrick, L.E.; Tuluc, F. Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism. J. Biol. Chem., 2009, 284(14), 9280-9289.
[http://dx.doi.org/10.1074/jbc.M808825200] [PMID: 19179340]
[108]
Lang, K.; Drell, T.L., IV; 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(2), 231-238.
[http://dx.doi.org/10.1002/ijc.20410] [PMID: 15352035]
[109]
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(3), 294-302.
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0609] [PMID: 23345604]
[110]
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(1-2), 48-56.
[http://dx.doi.org/10.1016/j.jneuroim.2005.03.016] [PMID: 15913794]
[111]
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(1), 306-318.
[http://dx.doi.org/10.1074/jbc.M112.389783] [PMID: 23166329]
[112]
Rodríguez, P.L.; Jiang, S.; Fu, Y.; Avraham, S.; Avraham, H.K. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Int. J. Cancer, 2014, 134(5), 1034-1044.
[http://dx.doi.org/10.1002/ijc.28433] [PMID: 23934616]
[113]
Lee, M.; McCloskey, M.; Staples, S. Prolonged use of aprepi-tant in metastatic breast cancer and a reduction in CA153 tu-mour marker levels. Int. J. Cancer Clin. Res, 2016. 06, 071.
[114]
Bielenberg, D.R.; Zetter, B.R. The contribution of angiogene-sis to the process of metastasis. Cancer J., 2015, 21(4), 267-273.
[http://dx.doi.org/10.1097/PPO.0000000000000138] [PMID: 26222078]
[115]
Orimo, A.; Weinberg, R.A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle, 2006, 5(15), 1597-1601.
[http://dx.doi.org/10.4161/cc.5.15.3112] [PMID: 16880743]
[116]
Watnick, R.S. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb. Perspect. Med., 2012, 2(12)a006676
[http://dx.doi.org/10.1101/cshperspect.a006676] [PMID: 23209177]
[117]
Deryugina, E.I.; Quigley, J.P. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol., 2015, 44-46, 94-112.
[http://dx.doi.org/10.1016/j.matbio.2015.04.004] [PMID: 25912949]
[118]
Amin, D.N.; Bielenberg, D.R.; Lifshits, E.; Heymach, J.V.; Klagsbrun, M. Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc. Res., 2008, 76(1), 15-22.
[http://dx.doi.org/10.1016/j.mvr.2008.01.002] [PMID: 18440031]
[119]
Ziche, M.; Morbidelli, L.; Pacini, M.; Geppetti, P.; Alessandri, G.; Maggi, C.A. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc. Res., 1990, 40(2), 264-278.
[http://dx.doi.org/10.1016/0026-2862(90)90024-L] [PMID: 1701206]
[120]
Kitchens, C.A.; McDonald, P.R.; Pollack, I.F.; Wipf, P.; Lazo, J.S. Synergy between microtubule destabilizing agents and neurokinin 1 receptor antagonists identified by an siRNA syn-thetic lethal screen. FASEB J., 2009, 23, 756-713.
[121]
Robinson, P.; Kasembeli, M.; Bharadwaj, U.; Engineer, N.; Eckols, K.T.; Tweardy, D.J. Substance P receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance. BioMed Res. Int., 2016.20161959270
[http://dx.doi.org/10.1155/2016/1959270] [PMID: 26981525]
[122]
Alfieri, A.B.; Cubeddu, L.X. Efectos de los antagonistas de los receptores NK1 y de la exametasona sobre la inflamación neurogénica inducida por ciclofosfamida y por radiación X, en la rata. AVFT, 2004, 23, 61-66.
[123]
Muñoz, M.; Coveñas, R. In: Encyclopedia of Endocrine Diseases; Huhtaniemi and Martini Eds.; Academic Press: Oxford; , 2019, pp. 571-578.
[124]
Muñoz, M.; Rosso, M.; Coveñas, R. In: Encyclopedia of Signaling Molecules; Choi, Ed.; Springer: Cham; , 2018, pp. 3437-3445.
[125]
Muñoz, M.; Rosso, M.; Coveñas, R. Neurokinin-1 receptor antagonists in lung cancer therapy. Lett. Drug Des. Discov., 2017, 14, 1465-1476.
[http://dx.doi.org/10.2174/1570180814666170327163854]
[126]
Maroñas-Jiménez, L.; Ortiz-Romero, P.L. Aprepitant did not modify global disease activity in cutaneous T-cell lymphomas. Br. J. Dermatol., 2018, 178, 1222-1223.
[127]
Maroñas-Jiménez, L.; Estrach, T.; Gallardo, F.; Pérez, A.; Andrés Borja, H.; Servitje, O.; Pérez Gala, S.; Linares Barrio, M.; Jiménez Gallo, D.; Sanz-Bueno, J.; Lora, D.; Monsálvez, V.; Ortiz-Romero, P.L. Aprepitant improves refractory pruritus in primary cutaneous T-cell lymphomas: experience of the Spanish Working Group on Cutaneous Lymphomas. Br. J. Dermatol., 2018, 178(4), e273-e274.
[http://dx.doi.org/10.1111/bjd.16128] [PMID: 29150837]
[128]
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(5383), 1640-1645.
[http://dx.doi.org/10.1126/science.281.5383.1640] [PMID: 9733503]
[129]
Keller, M.; Montgomery, S.; Ball, W.; Morrison, M.; Snavely, D.; Liu, G.; Hargreaves, R.; Hietala, J.; Lines, C.; Beebe, K.; Reines, S. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol. Psychiatry, 2006, 59(3), 216-223.
[http://dx.doi.org/10.1016/j.biopsych.2005.07.013] [PMID: 16248986]
[130]
Tebas, P.; Spitsin, S.; Barrett, J.S.; Tuluc, F.; Elci, O.; Korelitz, J.J.; Wagner, W.; Winters, A.; Kim, D.; Catalano, R.; Evans, D.L.; Douglas, S.D. Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults. AIDS, 2015, 29(8), 931-939.
[http://dx.doi.org/10.1097/QAD.0000000000000638] [PMID: 25915168]
[131]
Muñoz, M.; Martínez-Armesto, J.; Coveñas, R. NK-1 receptor antagonists as antitumor drugs: a survey of the literature from 2000 to 2011. Expert Opin. Ther. Pat., 2012, 22(7), 735-746.
[http://dx.doi.org/10.1517/13543776.2012.697153] [PMID: 22697287]
[132]
Muñoz, M. Use of non-peptide NK-1 receptor antagonists for the production of apoptosis in tumor cells. USPTO Application 20090012086 2004.
[133]
Ensayo clínico, fase II, de uso de aprepitant (antagonista de los receptores NK-1) en el tratamiento de pacientes con cáncer. Nº EudraCT 2005001585-13 2005.

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