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Central Nervous System Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Research Article

A Novel Highly Selective Cannabinoid CB2 Agonist Reduces in vitro Growth and TGF-beta Release of Human Glial Cell Tumors

Author(s): Chiara Cioni, Maristella Tassi, Giuseppe Marotta, Claudia Mugnaini, Federico Corelli* and Pasquale Annunziata*

Volume 19, Issue 3, 2019

Page: [206 - 214] Pages: 9

DOI: 10.2174/1871524919666190923154351

Abstract

Background: Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors.

Aims: To test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying a high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma.

Methods: Glioma cell cultures were established from two glioblastoma multiforme and two anaplastic astrocytomas. Proliferation was measured in the presence or absence of COR167 with a bromodeoxyuridine (BrdU) cell proliferation ELISA assay. CB2 receptor expression was detected by western blotting. Apoptosis was assessed with phycoerythrin (PE) annexin V flow cytometry kit. TGF-beta 1 and 2 levels were analyzed in culture supernatants with commercial ELISAs.

Results: COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with a significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures.

Conclusion: These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas.

Keywords: Glioma therapy, cannabinoids, CB2 receptor, TGF-beta, glioblastoma multiforme, anaplastic astrocytoma.

Graphical Abstract
[1]
Cohen, A.L.; Colman, H. Glioma biology and molecular markers Cancer Treat. Res, 2015, 163, 15-30.
[http://dx.doi.org/10.1007/978-3-319-12048-5_2] [PMID: 25468223]
[2]
Krex, D.; Klink, B.; Hartmann, C.; von Deimling, A.; Pietsch, T.; Simon, M.; Sabel, M.; Steinbach, J.P.; Heese, O.; Reifenberger, G.; Weller, M.; Schackert, G. Long-term survival with glioblastoma multiforme. Brain, 2007, 130(Pt 10), 2596-2606.
[http://dx.doi.org/10.1093/brain/awm204] [PMID: 17785346]
[3]
Binder, D.C.; Davis, A.A.; Wainwright, D.A. Immunotherapy for cancer in the central nervous system: Current and future directions. OncoImmunology, 2015, 5(2) e1082027
[http://dx.doi.org/10.1080/2162402X.2015.1082027] [PMID: 27057463]
[4]
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]
[5]
Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nat. Rev. Drug Discov., 2007, 6(4), 273-286.
[http://dx.doi.org/10.1038/nrd2115] [PMID: 17396134]
[6]
Held-Feindt, J.; Dörner, L.; Sahan, G.; Mehdorn, H.M.; Mentlein, R. Cannabinoid receptors in human astroglial tumors. J. Neurochem., 2006, 98(3), 886-893.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03911.x] [PMID: 16893424]
[7]
Ellert-Miklaszewska, A.; Grajkowska, W.; Gabrusiewicz, K.; Kaminska, B.; Konarska, L. Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res., 2007, 1137(1), 161-169.
[http://dx.doi.org/10.1016/j.brainres.2006.12.060] [PMID: 17239827]
[8]
Carracedo, A.; Lorente, M.; Egia, A.; Blázquez, C.; García, S.; Giroux, V.; Malicet, C.; Villuendas, R.; Gironella, M.; González-Feria, L.; Piris, M.A.; Iovanna, J.L.; Guzmán, M.; Velasco, G. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell, 2006, 9(4), 301-312.
[http://dx.doi.org/10.1016/j.ccr.2006.03.005] [PMID: 16616335]
[9]
Blázquez, C.; González-Feria, L.; Álvarez, L.; Haro, A.; Casanova, M.L.; Guzmán, M. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res., 2004, 64(16), 5617-5623.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3927] [PMID: 15313899]
[10]
Samoto, K.; Ikezaki, K.; Ono, M.; Shono, T.; Kohno, K.; Kuwano, M.; Fukui, M. Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res., 1995, 55(5), 1189-1193.
[PMID: 7532545]
[11]
Schmidt, N.O.; Westphal, M.; Hagel, C.; Ergün, S.; Stavrou, D.; Rosen, E.M.; Lamszus, K. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer, 1999, 84(1), 10-18.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19990219)84:1<10:AID-IJC3>3.0.CO;2-L] [PMID: 9988225]
[12]
Blázquez, C.; Salazar, M.; Carracedo, A.; Lorente, M.; Egia, A.; González-Feria, L.; Haro, A.; Velasco, G.; Guzmán, M. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res., 2008, 68(6), 1945-1952.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5176] [PMID: 18339876]
[13]
Casanova, M.L.; Blázquez, C.; Martínez-Palacio, J.; Villanueva, C.; Fernández-Aceñero, M.J.; Huffman, J.W.; Jorcano, J.L.; Guzmán, M. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J. Clin. Invest., 2003, 111(1), 43-50.
[http://dx.doi.org/10.1172/JCI200316116] [PMID: 12511587]
[14]
Sánchez, C.; de Ceballos, M.L.; Gomez del Pulgar, T.; Rueda, D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.; Huffman, J.W.; Ramón y Cajal, S.; Guzmán, M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res., 2001, 61(15), 5784-5789.
[PMID: 11479216]
[15]
Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.; Pertwee, R.G.; Ross, R.A.; Mechoulam, R.; Fride, E. HU-308: A specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA, 1999, 96(25), 14228-14233.
[http://dx.doi.org/10.1073/pnas.96.25.14228] [PMID: 10588688]
[16]
Huffman, J.W.; Liddle, J.; Yu, S.; Aung, M.M.; Abood, M.E.; Wiley, J.L.; Martin, B.R. 3-(1′,1′-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg. Med. Chem., 1999, 7(12), 2905-2914.
[http://dx.doi.org/10.1016/S0968-0896(99)00219-9] [PMID: 10658595]
[17]
Pasquini, S.; Botta, L.; Semeraro, T.; Mugnaini, C.; Ligresti, A.; Palazzo, E.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo. J. Med. Chem., 2008, 51(16), 5075-5084.
[http://dx.doi.org/10.1021/jm800552f] [PMID: 18680276]
[18]
Cascio, M.G.; Bolognini, D.; Pertwee, R.G.; Palazzo, E.; Corelli, F.; Pasquini, S.; Di Marzo, V.; Maione, S. In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB(2) receptor inverse agonists. Pharmacol. Res., 2010, 61(4), 349-354.
[http://dx.doi.org/10.1016/j.phrs.2009.11.011] [PMID: 19961936]
[19]
Annunziata, P.; Cioni, C.; Mugnaini, C.; Corelli, F. Potent immunomodulatory activity of a highly selective cannabinoid CB2 agonist on immune cells from healthy subjects and patients with multiple sclerosis. J. Neuroimmunol., 2017, 303, 66-74.
[http://dx.doi.org/10.1016/j.jneuroim.2016.12.009] [PMID: 28041663]
[20]
Brunet, J.F.; Pellerin, L.; Magistretti, P.; Villemure, J.G. Cryopreservation of human brain tissue allowing timely production of viable adult human brain cells for autologous transplantation. Cryobiology, 2003, 47(2), 179-183.
[http://dx.doi.org/10.1016/j.cryobiol.2003.08.005] [PMID: 14580852]
[21]
Mrsulja, B.B.; Mrsulja, B.J.; Fujimoto, T.; Klatzo, I.; Spatz, M. Isolation of brain capillaries: A simplified technique. Brain Res., 1976, 110(2), 361-365.
[http://dx.doi.org/10.1016/0006-8993(76)90408-X] [PMID: 938949]
[22]
Cioni, C.; Turlizzi, E.; Zanelli, U.; Oliveri, G.; Annunziata, P. Expression of tight junction and drug efflux transporter proteins in an in vitro model of human blood–brain barrier. Front. Psychiatry, 2012, 3, 47.
[http://dx.doi.org/10.3389/fpsyt.2012.00047] [PMID: 22593745]
[23]
Tada, H.; Shiho, O.; Kuroshima, K.; Koyama, M.; Tsukamoto, K. An improved colorimetric assay for interleukin 2. J. Immunol. Methods, 1986, 93(2), 157-165.
[http://dx.doi.org/10.1016/0022-1759(86)90183-3] [PMID: 3490518]
[24]
van der Zee, J.M.; Siegert, C.E.H.; de Vreede, T.A.; Daha, M.R.; Breedveld, F.C. Characterization of anti-endothelial cell antibodies in Systemic Lupus Erythematosus (SLE). Clin. Exp. Immunol., 1991, 84(2), 238-244.
[PMID: 2025951]
[25]
Schägger, H.; von Jagow, G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal. Biochem., 1987, 166(2), 368-379.
[http://dx.doi.org/10.1016/0003-2697(87)90587-2] [PMID: 2449095]
[26]
Galve-Roperh, I.; Sánchez, C.; Cortés, M.L.; Gómez del Pulgar, T.; Izquierdo, M.; Guzmán, M. Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med., 2000, 6(3), 313-319.
[http://dx.doi.org/10.1038/73171] [PMID: 10700234]
[27]
Sánchez, C.; Galve-Roperh, I.; Canova, C.; Brachet, P.; Guzmán, M. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett., 1998, 436(1), 6-10.
[http://dx.doi.org/10.1016/S0014-5793(98)01085-0] [PMID: 9771884]
[28]
Guzmán, M.; Sánchez, C.; Galve-Roperh, I. Control of the cell survival/death decision by cannabinoids. J. Mol. Med. (Berl.), 2001, 78(11), 613-625.
[http://dx.doi.org/10.1007/s001090000177] [PMID: 11269508]
[29]
Stella, N. Cannabinoid signaling in glial cells. Glia, 2004, 48(4), 267-277.
[http://dx.doi.org/10.1002/glia.20084] [PMID: 15390110]
[30]
Schley, M.; Ständer, S.; Kerner, J.; Vajkoczy, P.; Schüpfer, G.; Dusch, M.; Schmelz, M.; Konrad, C. Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res. Bull., 2009, 79(5), 333-337.
[http://dx.doi.org/10.1016/j.brainresbull.2009.01.011] [PMID: 19480992]
[31]
Fernández-Ruiz, J.; Romero, J.; Velasco, G.; Tolón, R.M.; Ramos, J.A.; Guzmán, M. Cannabinoid CB2 receptor: A new target for controlling neural cell survival? Trends Pharmacol. Sci., 2007, 28(1), 39-45.
[http://dx.doi.org/10.1016/j.tips.2006.11.001] [PMID: 17141334]
[32]
Palazuelos, J.; Aguado, T.; Egia, A.; Mechoulam, R.; Guzmán, M.; Galve-Roperh, I. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J., 2006, 20(13), 2405-2407.
[http://dx.doi.org/10.1096/fj.06-6164fje] [PMID: 17015409]
[33]
Guzmán, M.; Galve-Roperh, I.; Sánchez, C. Ceramide: A new second messenger of cannabinoid action. Trends Pharmacol. Sci., 2001, 22(1), 19-22.
[http://dx.doi.org/10.1016/S0165-6147(00)01586-8] [PMID: 11165667]
[34]
Carracedo, A.; Lorente, M.; Egia, A.; Blázquez, C.; García, S.; Giroux, V.; Malicet, C.; Villuendas, R.; Gironella, M.; González-Feria, L.; Piris, M.A.; Iovanna, J.L.; Guzmán, M.; Velasco, G. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell, 2006, 9(4), 301-312.
[http://dx.doi.org/10.1016/j.ccr.2006.03.005] [PMID: 16616335]
[35]
Massi, P.; Valenti, M.; Vaccani, A.; Gasperi, V.; Perletti, G.; Marras, E.; Fezza, F.; Maccarrone, M.; Parolaro, D. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J. Neurochem., 2008, 104(4), 1091-1100.
[http://dx.doi.org/10.1111/j.1471-4159.2007.05073.x] [PMID: 18028339]
[36]
Chang, H.L.; Gillett, N.; Figari, I.; Lopez, A.R.; Palladino, M.A.; Derynck, R. Increased transforming growth factor β expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells. Cancer Res., 1993, 53(18), 4391-4398.
[PMID: 8364935]
[37]
Cui, W.; Fowlis, D.J.; Bryson, S.; Duffie, E.; Ireland, H.; Balmain, A.; Akhurst, R.J. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell, 1996, 86(4), 531-542.
[http://dx.doi.org/10.1016/S0092-8674(00)80127-0] [PMID: 8752208]
[38]
Constam, D.B.; Philipp, J.; Malipiero, U.V.; ten Dijke, P.; Schachner, M.; Fontana, A. Differential expression of transforming growth factor-β 1, -β 2, and -β 3 by glioblastoma cells, astrocytes, and microglia. J. Immunol., 1992, 148(5), 1404-1410.
[PMID: 1538124]
[39]
Kjellman, C.; Olofsson, S.P.; Hansson, O.; Von Schantz, T.; Lindvall, M.; Nilsson, I.; Salford, L.G.; Sjögren, H.O.; Widegren, B. Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma. Int. J. Cancer, 2000, 89(3), 251-258.
[http://dx.doi.org/10.1002/1097-0215(20000520)89:3<251:AID-IJC7>3.0.CO;2-5] [PMID: 10861501]
[40]
Schneider, T.; Sailer, M.; Ansorge, S.; Firsching, R.; Reinhold, D. Increased concentrations of transforming growth factor beta1 and beta2 in the plasma of patients with glioblastoma. J. Neurooncol., 2006, 79(1), 61-65.
[http://dx.doi.org/10.1007/s11060-005-9116-7] [PMID: 16614941]
[41]
Pan, J.J.; Chang, W.J.; Barone, T.A.; Plunkett, R.J.; Ostrow, P.T.; Greenberg, S.J. Increased expression of TGF-β1 reduces tumor growth of human U-87 glioblastoma cells in vivo. Cancer Immunol. Immunother., 2006, 55(8), 918-927.
[http://dx.doi.org/10.1007/s00262-005-0083-9] [PMID: 16187082]
[42]
Ikushima, H.; Todo, T.; Ino, Y.; Takahashi, M.; Miyazawa, K.; Miyazono, K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell, 2009, 5(5), 504-514.
[http://dx.doi.org/10.1016/j.stem.2009.08.018] [PMID: 19896441]

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