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Current Pharmaceutical Design

Author(s): Sarapynbiang Marwein, Bijayashree Mishra, Utpal C. De and Pratap C. Acharya*

DOI: 10.2174/1381612825666190716141851

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Recent Progress of Adenosine Receptor Modulators in the Development of Anticancer Chemotherapeutic Agents

Page: [2842 - 2858] Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Increased risks of peripheral toxicity and undesired adverse effects associated with chemotherapeutic agents are the major medical hurdles in cancer treatment that worsen the quality of life of cancer patients. Although several novel and target-specific anticancer agents have been discovered in the recent past, none of them have proved to be effective in the management of metastatic tumor. Therefore, there is a continuous effort for the discovery of safer and effective cancer chemotherapeutic agent. Adenosine receptors have been identified as an important target to combat cancer because of their inherent role in the antitumor process. The antitumor property of the adenosine receptor is primarily attributed to their inherited immune response against the tumors. These findings have opened a new chapter in the anticancer drug discovery through adenosine receptor-mediated immunomodulation. This review broadly outlines the biological mechanism of adenosine receptors in mediating the selective cytotoxicity as well as the discovery of various classes of adenosine receptor modulators in the effective management of solid tumors.

Keywords: Adenosine receptors, immunomodulation, anticancer agents, hypoxia, angiogenesis, pro-tumoral and anti-tumoral effects, A3AR antagonist, A3AR agonists, A2AAR antagonists.

[1]
Bansal R, Acharya PC. Synthesis and antileukemic activity of 16E-[4-(2-carboxy)ethoxybenzylidene]-androstene amides. Steroids 2012; 77(5): 552-7.
[http://dx.doi.org/10.1016/j.steroids.2012.01.020] [PMID: 22326415]
[2]
Acharya PC, Bansal R, Kharkar PS. Hybrids of steroid and nitrogen mustard as antiproliferative agents: Synthesis, in vitro evaluation and in silico inverse screening. Drug Res 2018; 68(2): 100-3.
[http://dx.doi.org/10.1055/s-0043-118538] [PMID: 28950388]
[3]
Acharya PC, Bansal R. Synthesis and antiproliferative activity of hydroximino androstene derivatives. Arch Pharm Chem Life Sci 2014; 347: 193-9.
[http://dx.doi.org/10.1002/ardp.201300216] [PMID: 24343881]
[4]
Bansal R, Acharya PC. Man-made cytotoxic steroids: exemplary agents for cancer therapy. Chem Rev 2014; 114(14): 6986-7005.
[http://dx.doi.org/10.1021/cr4002935] [PMID: 24869712]
[5]
Acharya PC, Bansal R. Synthesis of androstene oxime-nitrogen mustard bioconjugates as potent antineoplastic agents. Steroids 2017; 123: 73-83.
[http://dx.doi.org/10.1016/j.steroids.2017.04.005] [PMID: 28450070]
[6]
Koebel CM, Vermi W, Swann JB, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450(7171): 903-7.
[http://dx.doi.org/10.1038/nature06309] [PMID: 18026089]
[7]
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331(6024): 1565-70.
[http://dx.doi.org/10.1126/science.1203486] [PMID: 21436444]
[8]
Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 2006; 103(35): 13132-7.
[http://dx.doi.org/10.1073/pnas.0605251103] [PMID: 16916931]
[9]
Ohta A, Ohta A, Madasu M, et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 2009; 183(9): 5487-93.
[http://dx.doi.org/10.4049/jimmunol.0901247] [PMID: 19843934]
[10]
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001; 53(4): 527-52.
[PMID: 11734617]
[11]
Deb PK, Mailavaram R, Chandrasekaran B, et al. Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3-d]pyrimidine derivatives. Chem Biol Drug Des 2018; 91(4): 962-9.
[http://dx.doi.org/10.1111/cbdd.13155] [PMID: 29194979]
[12]
Pran Kishore D, Balakumar C, Raghuram Rao A, Roy PP, Roy K. QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A(3) receptor subtype. Bioorg Med Chem Lett 2011; 21(2): 818-23.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.094] [PMID: 21163647]
[13]
Baldwin JM. Structure and function of receptors coupled to G proteins. Curr Opin Cell Biol 1994; 6(2): 180-90.
[http://dx.doi.org/10.1016/0955-0674(94)90134-1] [PMID: 8024808]
[14]
Schöneberg T, Schulz A, Gudermann T. The structural basis of G-protein-coupled receptor function and dysfunction in human diseases. Rev Physiol Biochem Pharmacol 2002; 144: 143-227.
[http://dx.doi.org/10.1007/BFb0116587] [PMID: 11987825]
[15]
Shaik K, Deb PK, Mailavaram RP, Chandrasekaran B, Kachler S, Klotz KN. Yousef Jaber Am. 7-Amino-2-aryl/heteroaryl-5-oxo-5, 8-dihydro[1, 2, 4] triazolo[1, 5-a]pyridine-6-carbonitriles: Synthesis and Adenosine Receptor Binding Studies. Chem Biol Drug Des 2019; 94(2): 1568-73.
[http://dx.doi.org/10.1111/cbdd.13528]
[16]
Cunha RA. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 2001; 38(2): 107-25.
[http://dx.doi.org/10.1016/S0197-0186(00)00034-6] [PMID: 11137880]
[17]
Paes-De-Carvalho R. Adenosine as a signaling molecule in the retina: Biochemical and developmental aspects. An Acad Bras Cienc 2002; 74(3): 437-51.
[18]
Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells. Int J Oncol 2008; 32(3): 527-35.
[http://dx.doi.org/10.3892/ijo.32.3.527] [PMID: 18292929]
[19]
Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 2000; 287(5458): 1606-9.
[http://dx.doi.org/10.1126/science.287.5458.1606] [PMID: 10733430]
[20]
Madi L, Ochaion A, Rath-Wolfson L, et al. The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin Cancer Res 2004; 10(13): 4472-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-03-0651] [PMID: 15240539]
[21]
Gessi S, Cattabriga E, Avitabile A, et al. Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res 2004; 10(17): 5895-901.
[http://dx.doi.org/10.1158/1078-0432.CCR-1134-03] [PMID: 15355922]
[22]
Bar-Yehuda S, Stemmer SM, Madi L, et al. The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways. Int J Oncol 2008; 33(2): 287-95.
[PMID: 18636149]
[23]
Khoo HE, Ho CL, Chhatwal VJ, Chan ST, Ngoi SS, Moochhala SM. Differential expression of adenosine A1 receptors in colorectal cancer and related mucosa. Cancer Lett 1996; 106(1): 17-21.
[http://dx.doi.org/10.1016/0304-3835(96)04289-9] [PMID: 8827042]
[24]
Gessi S, Varani K, Merighi S, et al. Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells. Br J Pharmacol 2001; 134(1): 116-26.
[http://dx.doi.org/10.1038/sj.bjp.0704254] [PMID: 11522603]
[25]
Merighi S, Varani K, Gessi S, et al. Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line. Br J Pharmacol 2001; 134(6): 1215-26.
[http://dx.doi.org/10.1038/sj.bjp.0704352] [PMID: 11704641]
[26]
D’Ancona S, Ragazzi E, Fassina G, Mazzo M, Gusella M, Berti T. Effect of dipyridamole, 5′-(N-ethyl)-carboxamidoadenosine and 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine on LOVO cell growth and morphology. Anticancer Res 1994; 14(1A): 93-7.
[PMID: 8166462]
[27]
Shaban M, Smith RA, Stone TW. Purine suppression of proliferation of Sertoli-like TM4 cells in culture. Cell Prolif 1995; 28(12): 673-82.
[http://dx.doi.org/10.1111/j.1365-2184.1995.tb00053.x] [PMID: 8634374]
[28]
Mirza A, Basso A, Black S, et al. RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Cancer Biol Ther 2005; 4(12): 1355-60.
[http://dx.doi.org/10.4161/cbt.4.12.2196] [PMID: 16294023]
[29]
Sai K, Yang D, Yamamoto H, et al. A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. Neurotoxicology 2006; 27(4): 458-67.
[http://dx.doi.org/10.1016/j.neuro.2005.12.008] [PMID: 16469385]
[30]
Dehnhardt M, Palm C, Vieten A, Bauer A, Pietrzyk U. Quantifying the A1AR distribution in peritumoural zones around experimental F98 and C6 rat brain tumours. J Neurooncol 2007; 85(1): 49-63.
[http://dx.doi.org/10.1007/s11060-007-9391-6] [PMID: 17497078]
[31]
Castillo CA, Albasanz JL, Fernández M, Martín M. Endogenous expression of adenosine A1, A2 and A3 receptors in rat C6 glioma cells. Neurochem Res 2007; 32(6): 1056-70.
[http://dx.doi.org/10.1007/s11064-006-9273-x] [PMID: 17401671]
[32]
Synowitz M, Glass R, Färber K, et al. A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res 2006; 66(17): 8550-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0365] [PMID: 16951167]
[33]
Saito M, Yaguchi T, Yasuda Y, Nakano T, Nishizaki T. Adenosine suppresses CW2 human colonic cancer growth by inducing apoptosis via A(1) adenosine receptors. Cancer Lett 2010; 290(2): 211-5.
[http://dx.doi.org/10.1016/j.canlet.2009.09.011] [PMID: 19822392]
[34]
Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: a potent suppressor of antitumor immune responses. Trends Immunol 2012; 33(5): 231-7.
[http://dx.doi.org/10.1016/j.it.2012.02.009] [PMID: 22487321]
[35]
Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol 2016; 29: 90-6.
[http://dx.doi.org/10.1016/j.coph.2016.06.009] [PMID: 27429212]
[36]
Gessi S, Varani K, Merighi S, et al. A(3) adenosine receptors in human neutrophils and promyelocytic HL60 cells: a pharmacological and biochemical study. Mol Pharmacol 2002; 61(2): 415-24.
[http://dx.doi.org/10.1124/mol.61.2.415] [PMID: 11809867]
[37]
Hillion J, Canals M, Torvinen M, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 2002; 277(20): 18091-7.
[http://dx.doi.org/10.1074/jbc.M107731200] [PMID: 11872740]
[38]
Mundell SJ, Kelly E. Evidence for co-expression and desensitization of A2a and A2b adenosine receptors in NG108-15 cells. Biochem Pharmacol 1998; 55(5): 595-603.
[http://dx.doi.org/10.1016/S0006-2952(97)00466-8] [PMID: 9515570]
[39]
Mayne M, Fotheringham J, Yan HJ, et al. Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann Neurol 2001; 49(6): 727-35.
[http://dx.doi.org/10.1002/ana.1010] [PMID: 11409424]
[40]
van der Ploeg I, Ahlberg S, Parkinson FE, Olsson RA, Fredholm BB. Functional characterization of adenosine A2 receptors in Jurkat cells and PC12 cells using adenosine receptor agonists. Naunyn Schmiedebergs Arch Pharmacol 1996; 353(3): 250-60.
[http://dx.doi.org/10.1007/BF00168626] [PMID: 8692279]
[41]
Tey HB, Khoo HE, Tan CH. Adenosine modulates cell growth in human epidermoid carcinoma (A431) cells. Biochem Biophys Res Commun 1992; 187(3): 1486-92.
[http://dx.doi.org/10.1016/0006-291X(92)90470-6] [PMID: 1417825]
[42]
Gessi S, Merighi S, Varani K, et al. Adenosine receptors in colon carcinoma tissues and colon tumoral cell lines: focus on the A(3) adenosine subtype. J Cell Physiol 2007; 211(3): 826-36.
[http://dx.doi.org/10.1002/jcp.20994] [PMID: 17348028]
[43]
Gessi S, Sacchetto V, Fogli E, et al. Modulation of metalloproteinase-9 in U87MG glioblastoma cells by A3 adenosine receptors. Biochem Pharmacol 2010; 79(10): 1483-95.
[http://dx.doi.org/10.1016/j.bcp.2010.01.009] [PMID: 20096265]
[44]
Etique N, Grillier-Vuissoz I, Lecomte J, Flament S. Crosstalk between adenosine receptor (A2A isoform) and ERalpha mediates ethanol action in MCF-7 breast cancer cells. Oncol Rep 2009; 21(4): 977-81.
[PMID: 19287996]
[45]
Koshiba M, Kojima H, Huang S, Apasov S, Sitkovsky MV. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 1997; 272(41): 25881-9.
[http://dx.doi.org/10.1074/jbc.272.41.25881] [PMID: 9325320]
[46]
Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells. Int J Oncol 2008; 32(3): 527-35.
[http://dx.doi.org/10.3892/ijo.32.3.527] [PMID: 18292929]
[47]
Lappas CM, Rieger JM, Linden J. A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 2005; 174(2): 1073-80.
[http://dx.doi.org/10.4049/jimmunol.174.2.1073] [PMID: 15634932]
[48]
Naganuma M, Wiznerowicz EB, Lappas CM, Linden J, Worthington MT, Ernst PB. Cutting edge: Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol 2006; 177(5): 2765-9.
[http://dx.doi.org/10.4049/jimmunol.177.5.2765] [PMID: 16920910]
[49]
Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204(6): 1257-65.
[http://dx.doi.org/10.1084/jem.20062512] [PMID: 17502665]
[50]
Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50(3): 413-92.
[PMID: 9755289]
[51]
Merighi S, Mirandola P, Milani D, et al. Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J Invest Dermatol 2002; 119(4): 923-33.
[http://dx.doi.org/10.1046/j.1523-1747.2002.00111.x] [PMID: 12406340]
[52]
Montesinos MC, Desai A, Chen JF, et al. Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A(2A) receptors. Am J Pathol 2002; 160(6): 2009-18.
[http://dx.doi.org/10.1016/S0002-9440(10)61151-0] [PMID: 12057906]
[53]
Yasuda Y, Saito M, Yamamura T, Yaguchi T, Nishizaki T. Extracellular adenosine induces apoptosis in Caco-2 human colonic cancer cells by activating caspase-9/-3 via A(2a) adenosine receptors. J Gastroenterol 2009; 44(1): 56-65.
[http://dx.doi.org/10.1007/s00535-008-2273-7] [PMID: 19159073]
[54]
Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2014; 2(7): 598-605.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0075] [PMID: 24990240]
[55]
Williams BA, Manzer A, Blay J, Hoskin DW. Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells. Biochem Biophys Res Commun 1997; 231(2): 264-9.
[http://dx.doi.org/10.1006/bbrc.1997.6077] [PMID: 9070261]
[56]
Hoskin DW, Butler JJ, Drapeau D, Haeryfar SMM, Blay J. Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. Int J Cancer 2002; 99(3): 386-95.
[http://dx.doi.org/10.1002/ijc.10325] [PMID: 11992407]
[57]
Mediavilla-Varela M, Luddy K, Noyes D, et al. Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol Ther 2013; 14(9): 860-8.
[http://dx.doi.org/10.4161/cbt.25643] [PMID: 23917542]
[58]
Fredholm BB. Adenosine receptors as drug targets. Exp Cell Res 2010; 316(8): 1284-8.
[http://dx.doi.org/10.1016/j.yexcr.2010.02.004] [PMID: 20153317]
[59]
Deb PK, Chandrasekaran B, Mailavaram R, Tekade RK, Jaber AMY. Molecular modeling approaches for the discovery of adenosine A2B receptor antagonists: current status and future perspectives. Drug Discov Today 2019.S1359-6446(19): 30045-5
[http://dx.doi.org/10.1016/j.drudis.2019.05.011] [PMID: 31103731]
[60]
Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res 2003; 92(5): 485-92.
[http://dx.doi.org/10.1161/01.RES.0000061572.10929.2D] [PMID: 12600879]
[61]
Merighi S, Benini A, Mirandola P, et al. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol 2007; 72(2): 395-406.
[http://dx.doi.org/10.1124/mol.106.032920] [PMID: 17488804]
[62]
Feoktistov I, Goldstein AE, Ryzhov S, et al. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res 2002; 90(5): 531-8.
[http://dx.doi.org/10.1161/01.RES.0000012203.21416.14] [PMID: 11909816]
[63]
Zeng D, Maa T, Wang U, Feoktistov I, Biaggioni I, Belardinelli L. Expression and function of A2B adenosine receptors in the U87MG tumor cells. Drug Dev Res 2003; 58: 405-11.
[http://dx.doi.org/10.1002/ddr.10212]
[64]
Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene 2007; 26(22): 3100-12.
[http://dx.doi.org/10.1038/sj.onc.1210392] [PMID: 17496909]
[65]
Fredholm BB, Irenius E, Kull B, Schulte G. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 2001; 61(4): 443-8.
[http://dx.doi.org/10.1016/S0006-2952(00)00570-0] [PMID: 11226378]
[66]
Bieber D, Lorenz K, Yadav R, Klotz KN. A2B adenosine receptors mediate an inhibition of ERK-1/2 phosphorylation in the breast cancer cell line MDA-MB-231. Naunyn Schmiedebergs Arch Pharmacol 2008; 377: 1-98.
[67]
Svensson S, Jirström K, Rydén L, et al. ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 2005; 24(27): 4370-9.
[http://dx.doi.org/10.1038/sj.onc.1208626] [PMID: 15806151]
[68]
Mittal D, Sinha D, Barkauskas D, et al. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res 2016; 76(15): 4372-82.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0544] [PMID: 27221704]
[69]
Desmet CJ, Gallenne T, Prieur A, et al. Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc Natl Acad Sci USA 2013; 110(13): 5139-44.
[http://dx.doi.org/10.1073/pnas.1222085110] [PMID: 23483055]
[70]
Fishman P, Bar-Yehuda S, Vagman L. Adenosine and other low molecular weight factors released by muscle cells inhibit tumor cell growth. Cancer Res 1998; 58(14): 3181-7.
[PMID: 9679987]
[71]
Leibovich SJ, Chen JF, Pinhal-Enfield G, et al. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 2002; 160(6): 2231-44.
[http://dx.doi.org/10.1016/S0002-9440(10)61170-4] [PMID: 12057925]
[72]
Yao Y, Sei Y, Abbracchio MP, Jiang JL, Kim YC, Jacobson KA. Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists. Biochem Biophys Res Commun 1997; 232(2): 317-22.
[http://dx.doi.org/10.1006/bbrc.1997.6290] [PMID: 9125172]
[73]
Jacobson KA. Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol Sci 1998; 19(5): 184-91.
[http://dx.doi.org/10.1016/S0165-6147(98)01203-6] [PMID: 9652191]
[74]
Gao Z, Li BS, Day YJ, Linden J. A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol Pharmacol 2001; 59(1): 76-82.
[http://dx.doi.org/10.1124/mol.59.1.76] [PMID: 11125027]
[75]
Merighi S, Benini A, Mirandola P, et al. A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells. J Biol Chem 2005; 280(20): 19516-26.
[http://dx.doi.org/10.1074/jbc.M413772200] [PMID: 15774470]
[76]
Nakamura K, Yoshikawa N, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Antitumor effect of cordycepin (3′-deoxyadenosine) on mouse melanoma and lung carcinoma cells involves adenosine A3 receptor stimulation. Anticancer Res 2006; 26(1A): 43-7.
[PMID: 16475677]
[77]
Fishman P, Bar-Yehuda S, Ohana G, et al. Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the A3 adenosine receptor. Eur J Cancer 2000; 36(11): 1452-8.
[http://dx.doi.org/10.1016/S0959-8049(00)00130-1] [PMID: 10899660]
[78]
Fishman P, Bar-Yehuda S, Ohana G, et al. An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3 β and NF-kappa B. Oncogene 2004; 23(14): 2465-71.
[http://dx.doi.org/10.1038/sj.onc.1207355] [PMID: 14691449]
[79]
Abbracchio MP, Brambilla R, Ceruti S, et al. G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. Mol Pharmacol 1995; 48(6): 1038-45.
[PMID: 8848003]
[80]
Murthy KS, Makhlouf GM. Adenosine A1 receptor-mediated activation of phospholipase C-beta 3 in intestinal muscle: dual requirement for alpha and beta gamma subunits of Gi3. Mol Pharmacol 1995; 47(6): 1172-9.
[PMID: 7603457]
[81]
Olah ME, Stiles GL. Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol 1995; 35: 581-606.
[http://dx.doi.org/10.1146/annurev.pa.35.040195.003053] [PMID: 7598508]
[82]
Olah ME, Ren H, Stiles GL. Adenosine receptors: protein and gene structure. Arch Int Pharmacodyn Ther 1995; 329(1): 135-50.
[PMID: 7639615]
[83]
Poulsen SA, Quinn RJ. Adenosine receptors: new opportunities for future drugs. Bioorg Med Chem 1998; 6(6): 619-41.
[http://dx.doi.org/10.1016/S0968-0896(98)00038-8] [PMID: 9681130]
[84]
Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 2005; 85(4): 1303-42.
[http://dx.doi.org/10.1152/physrev.00001.2005] [PMID: 16183914]
[85]
Zhao Z, Makaritsis K, Francis CE, Gavras H, Ravid K. A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies in knock-out mice. Biochim Biophys Acta 2000; 1500(3): 280-90.
[http://dx.doi.org/10.1016/S0925-4439(99)00111-8] [PMID: 10699369]
[86]
Jajoo S, Mukherjea D, Watabe K, Ramkumar V. Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 2009; 11(11): 1132-45.
[http://dx.doi.org/10.1593/neo.09744] [PMID: 19881949]
[87]
Mirandola P, Ponti C, Gobbi G, et al. Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity. Blood 2004; 104(8): 2418-24.
[http://dx.doi.org/10.1182/blood-2004-04-1294] [PMID: 15205263]
[88]
Harish A, Hohana G, Fishman P, Arnon O, Bar-Yehuda S. A3 adenosine receptor agonist potentiates natural killer cell activity. Int J Oncol 2003; 23(4): 1245-9.
[http://dx.doi.org/10.3892/ijo.23.4.1245] [PMID: 12964011]
[89]
Merighi S, Benini A, Mirandola P, et al. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol 2006; 72(1): 19-31.
[http://dx.doi.org/10.1016/j.bcp.2006.03.020] [PMID: 16682012]
[90]
Merighi S, Benini A, Mirandola P, et al. A3 adenosine receptors modulate hypoxia-inducible factor-1α expression in human A375 melanoma cells. Neoplasia 2005; 7(10): 894-903.
[http://dx.doi.org/10.1593/neo.05334] [PMID: 16242072]
[91]
Merighi S, Benini A, Mirandola P, et al. Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol 2007; 72(1): 162-72.
[http://dx.doi.org/10.1124/mol.106.031849] [PMID: 17400763]
[92]
Welsh SJ, Powis G. Hypoxia inducible factor as a cancer drug target. Curr Cancer Drug Targets 2003; 3(6): 391-405.
[http://dx.doi.org/10.2174/1568009033481732] [PMID: 14683498]
[93]
Höpfl G, Ogunshola O, Gassmann M. HIFs and tumors-causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004; 286(4): R608-23.
[http://dx.doi.org/10.1152/ajpregu.00538.2003] [PMID: 15003941]
[94]
Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA. Adenosine receptors and cancer. Biochim Biophys Acta 2011; 1808(5): 1400-12.
[http://dx.doi.org/10.1016/j.bbamem.2010.09.020] [PMID: 20888788]
[95]
Fishman P, Bar-Yehuda S, Farbstein T, Barer F, Ohana G. Adenosine acts as a chemoprotective agent by stimulating G-CSF production: a role for A1 and A3 adenosine receptors. J Cell Physiol 2000; 183(3): 393-8.
[http://dx.doi.org/10.1002/(SICI)1097-4652(200006)183:3<393:AID-JCP12>3.0.CO;2-G] [PMID: 10797314]
[96]
Fishman P, Bar-Yehuda S, Barer F, Madi L, Multani AS, Pathak S. The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 2001; 269(2): 230-6.
[http://dx.doi.org/10.1006/excr.2001.5327] [PMID: 11570815]
[97]
Fishman P, Bar-Yehuda S, Madi L, Cohn I. A3 adenosine receptor as a target for cancer therapy. Anticancer Drugs 2002; 13(5): 437-43.
[http://dx.doi.org/10.1097/00001813-200206000-00001] [PMID: 12045454]
[98]
Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L, Khalili K. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 2002; 21(25): 4060-4.
[http://dx.doi.org/10.1038/sj.onc.1205531] [PMID: 12037688]
[99]
Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L, Khalili K. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 2002; 21(25): 4060-4.
[http://dx.doi.org/10.1038/sj.onc.1205531] [PMID: 12037688]
[100]
Fishman P, Bar-Yehuda S, Ardon E, et al. Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist. Anticancer Res 2003; 23(3A): 2077-83.
[PMID: 12894581]
[101]
Bar-Yehuda S, Barer F, Volfsson L, Fishman P. Resistance of muscle to tumor metastases: a role for a3 adenosine receptor agonists. Neoplasia 2001; 3(2): 125-31.
[http://dx.doi.org/10.1038/sj.neo.7900138] [PMID: 11420748]
[102]
Merimsky O, Bar-Yehuda S, Madi L, Fishman P. Modulation of the A3 adenosine receptor by low agonist concentration induced antitumor and myelostimulation effects. Drug Dev Res 2003; 58: 386-9.
[http://dx.doi.org/10.1002/ddr.10182]
[103]
Ohana G, Bar-Yehuda S, Arich A, et al. Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101. Br J Cancer 2003; 89(8): 1552-8.
[http://dx.doi.org/10.1038/sj.bjc.6601315] [PMID: 14562031]
[104]
Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A, Fishman P. A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. J Biol Chem 2003; 278(43): 42121-30.
[http://dx.doi.org/10.1074/jbc.M301243200] [PMID: 12865431]
[105]
Franchetti P, Grifantini M. Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents. Curr Med Chem 1999; 6(7): 599-614.
[PMID: 10390603]
[106]
Cappellacci L, Barboni G, Franchetti P, Martini C, Jayaram HN, Grifantini M. A new tiazofurin pronucleotide: synthesis and biological evaluation of cyclosaligenyl-tiazofurin monophosphate. Nucleosides Nucleotides Nucleic Acids 2003; 22(5-8): 869-72.
[http://dx.doi.org/10.1081/NCN-120022674] [PMID: 14565299]
[107]
Markovic DS, Glass R, Synowitz M. Rooijen Nv, Kettenmann H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 2005; 64(9): 754-62.
[http://dx.doi.org/10.1097/01.jnen.0000178445.33972.a9] [PMID: 16141784]
[108]
Zhou Y, Tong L, Chu X, et al. The Adenosine A1 Receptor Antagonist DPCPX Inhibits Tumor Progression via the ERK/JNK Pathway in Renal Cell Carcinoma. Cell Physiol Biochem 2017; 43(2): 733-42.
[http://dx.doi.org/10.1159/000481557] [PMID: 28950257]
[109]
Klotz KN. Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol 2000; 362(4-5): 382-91.
[http://dx.doi.org/10.1007/s002100000315] [PMID: 11111832]
[110]
Varani K, Merighi S, Gessi S, et al. [(3)H]MRE 3008F20: a novel antagonist radioligand for the pharmacological and biochemical characterization of human A(3) adenosine receptors. Mol Pharmacol 2000; 57(5): 968-75.
[PMID: 10779381]
[111]
Merighi S, Mirandola P, Varani K, et al. A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 2003; 100(1): 31-48.
[http://dx.doi.org/10.1016/S0163-7258(03)00084-6] [PMID: 14550503]
[112]
Muller-Haegele S, Muller L, Whiteside TL. Immunoregulatory activity of adenosine and its role in human cancer progression. Expert Rev Clin Immunol 2014; 10(7): 897-914.
[http://dx.doi.org/10.1586/1744666X.2014.915739] [PMID: 24871693]
[113]
Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 2008; 14(19): 5947-52.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0229] [PMID: 18829471]
[114]
Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 2016; 30(3): 391-403.
[http://dx.doi.org/10.1016/j.ccell.2016.06.025] [PMID: 27622332]
[115]
Perez-Aso M, Mediero A, Low YC, Levine J, Cronstein BN. Adenosine A2A receptor plays an important role in radiation-induced dermal injury. FASEB J 2016; 30(1): 457-65.
[http://dx.doi.org/10.1096/fj.15-280388] [PMID: 26415936]
[116]
Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am J Cancer Res 2014; 4(2): 172-81.
[PMID: 24660106]
[117]
Beavis PA, Divisekera U, Paget C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci USA 2013; 110(36): 14711-6.
[http://dx.doi.org/10.1073/pnas.1308209110] [PMID: 23964122]
[118]
Jin D, Fan J, Wang L, et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 2010; 70(6): 2245-55.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3109] [PMID: 20179192]
[119]
Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T cell responses. Cancer Immunol Res 2015; 3(5): 506-17.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0211] [PMID: 25672397]
[120]
Gessi S, Bencivenni S, Battistello E, et al. Inhibition of A2A adenosine receptor signaling in cancer cells proliferation by the novel antagonist TP455. Front Pharmacol 2017; 8: 888-901.
[http://dx.doi.org/10.3389/fphar.2017.00888] [PMID: 29249971]
[121]
Willingham S, Ho P, Leone R, et al. The adenosine A2A receptor antagonist CPI-444 blocks adenosine-mediated T-cell suppression and exhibits antitumor activity alone and in combination with anti-PD-1 and anti-PD-L1. abstract Proceedings of the 107th Annual Meeting of the American Association for Cancer Research. 2016 Apr 16-20; New Orleans, LA. 2016.
[122]
McCaffery I, Laport G, Hotson A, et al. Biomarker and clinical activity of CPI-444, a novel small molecule inhibitor of A2A receptor (A2AR), in a Ph1b study in advanced cancers. Ann Oncol 2016; 27(Suppl. 6): vi114-35.
[http://dx.doi.org/10.1093/annonc/mdw368.32]
[123]
Mediavilla-Varela M, Castro J, Chiappori A, et al. A novel antagonist of the immune checkpoint protein adenosine A2a receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment. Neoplasia 2017; 19(7): 530-6.
[http://dx.doi.org/10.1016/j.neo.2017.02.004] [PMID: 28582704]
[124]
Borodovsky A, Wang Y, Ye M, et al. Inhibition of A R by AZD4635 induces anti-tumor immunity alone and in combination with anti-PDL1 in preclinical models [abstract] Proceedings of the American Association for Cancer Research Annual Meeting. 2018 Apr 14-18; Chicago, IL. 2018.
[125]
Jafari SM, Joshaghani HR, Panjehpour M, Aghaei M. A2B adenosine receptor agonist induces cell cycle arrest and apoptosis in breast cancer stem cells via ERK1/2 phosphorylation. Cell Oncol 2018; 41(1): 61-72.
[http://dx.doi.org/10.1007/s13402-017-0359-z] [PMID: 29218545]
[126]
Ryzhov S, Novitskiy SV, Zaynagetdinov R, et al. Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia 2008; 10(9): 987-95.
[http://dx.doi.org/10.1593/neo.08478] [PMID: 18714400]
[127]
Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 2013; 15(12): 1400-9.
[http://dx.doi.org/10.1593/neo.131748] [PMID: 24403862]
[128]
Sorrentino C, Miele L, Porta A, Pinto A, Morello S. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression. Oncotarget 2016; 7(39): 64274-88.
[http://dx.doi.org/10.18632/oncotarget.11729] [PMID: 27590504]
[129]
Morello S, Miele L. Targeting the adenosine A2b receptor in the tumor microenvironment overcomes local immunosuppression by myeloid-derived suppressor cells. OncoImmunology 2014; 3e27989
[http://dx.doi.org/10.4161/onci.27989] [PMID: 25101221]
[130]
Kaji W, Tanaka S, Tsukimoto M, Kojima S. Adenosine A(2B) receptor antagonist PSB603 suppresses tumor growth and metastasis by inhibiting induction of regulatory T cells. J Toxicol Sci 2014; 39(2): 191-8.
[http://dx.doi.org/10.2131/jts.39.191] [PMID: 24646699]
[131]
Mølck C, Ryall J, Failla LM, et al. The A2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism. Cancer Lett 2016; 383(1): 135-43.
[http://dx.doi.org/10.1016/j.canlet.2016.09.018] [PMID: 27693637]
[132]
Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA. Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 2012; 17(7-8): 359-66.
[http://dx.doi.org/10.1016/j.drudis.2011.10.007] [PMID: 22033198]
[133]
Fishman P, Jacobson KA, Ochaion A, Cohen S, Bar-Yehuda S. The anti-cancer effect of A3 adenosine receptor agonists: a novel targeted therapy. Immunol Endocr Metab Agents Med Chem 2007; 7: 298-303.
[http://dx.doi.org/10.2174/187152207781369878]
[134]
Jeong LS, Kim MJ, Kim HO, et al. Design and synthesis of 3′-ureidoadenosine-5′-uronamides: effects of the 3′-ureido group on binding to the A3 adenosine receptor. Bioorg Med Chem Lett 2004; 14(19): 4851-4.
[http://dx.doi.org/10.1016/j.bmcl.2004.07.042] [PMID: 15341938]
[135]
Joshi BV, Jacobson KA. Purine derivatives as ligands for A3 adenosine receptors. Curr Top Med Chem 2005; 5(13): 1275-95.
[http://dx.doi.org/10.2174/156802605774463079] [PMID: 16305531]
[136]
Bar-Yehuda S, Madi L, Silberman D, Gery S, Shkapenuk M, Fishman P. CF101, an agonist to the A3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a colon carcinoma murine model. Neoplasia 2005; 7(1): 85-90.
[http://dx.doi.org/10.1593/neo.04364] [PMID: 15720820]
[137]
Joshaghani HR, Jafari SM, Aghaei M, Panjehpour M, Abedi H. A3 adenosine receptor agonist induce G1 cell cycle arrest via Cyclin D and cyclin-dependent kinase 4 pathways in OVCAR-3 and Caov-4 cell lines. J Cancer Res Ther 2017; 13(1): 107-12.
[http://dx.doi.org/10.4103/0973-1482.199381] [PMID: 28508842]
[138]
Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A, Fishman P. A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. J Biol Chem 2003; 278(43): 42121-30.
[http://dx.doi.org/10.1074/jbc.M301243200] [PMID: 12865431]
[139]
Cohen S, Stemmer SM, Zozulya G, et al. CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol 2011; 226(9): 2438-47.
[http://dx.doi.org/10.1002/jcp.22593] [PMID: 21660967]
[140]
Lee EJ, Min HY, Chung HJ, et al. A novel adenosine analog, thio-Cl-IB-MECA, induces G0/G1 cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells. Biochem Pharmacol 2005; 70(6): 918-24.
[http://dx.doi.org/10.1016/j.bcp.2005.06.017] [PMID: 16051194]
[141]
Chung H, Jung JY, Cho SD, et al. The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. Mol Cancer Ther 2006; 5(3): 685-92.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0245] [PMID: 16546983]
[142]
Nakamura K, Shinozuka K, Yoshikawa N. Anticancer and antimetastatic effects of cordycepin, an active component of Cordyceps sinensis. J Pharmacol Sci 2015; 127(1): 53-6.
[http://dx.doi.org/10.1016/j.jphs.2014.09.001] [PMID: 25704018]
[143]
Cao HL, Liu ZJ, Chang Z. Cordycepin induces apoptosis in human bladder cancer cells via activation of A3 adenosine receptors. Tumour Biol 2017; 39(7)1010428317706915
[http://dx.doi.org/10.1177/1010428317706915] [PMID: 28714368]
[144]
Blad CC, von Frijtag DKJK, de Vries H, et al. Putative role of the adenosine A(3) receptor in the antiproliferative action of N (6)-(2-isopentenyl)adenosine. Purinergic Signal 2011; 7(4): 453-62.
[http://dx.doi.org/10.1007/s11302-011-9244-9] [PMID: 21720785]
[145]
Polycarpou E, Meira LB, Carrington S, Tyrrell E, Modjtahedi H, Carew MA. Resveratrol 3-O-D-glucuronide and resveratrol 4′-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest. Mol Nutr Food Res 2013; 57(10): 1708-17.
[http://dx.doi.org/10.1002/mnfr.201200742] [PMID: 23650147]
[146]
Aires V, Limagne E, Cotte AK, Latruffe N, Ghiringhelli F, Delmas D. Resveratrol metabolites inhibit human metastatic colon cancer cells progression and synergize with chemotherapeutic drugs to induce cell death. Mol Nutr Food Res 2013; 57(7): 1170-81.
[http://dx.doi.org/10.1002/mnfr.201200766] [PMID: 23495229]
[147]
Ayoub BM, Attia YM, Ahmed MS. Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma. J Enzyme Inhib Med Chem 2018; 33(1): 858-66.
[http://dx.doi.org/10.1080/14756366.2018.1462801] [PMID: 29768061]
[148]
Gessi S, Merighi S, Varani K, Leung E, Mac Lennan S, Borea PA. The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 2008; 117(1): 123-40.
[http://dx.doi.org/10.1016/j.pharmthera.2007.09.002] [PMID: 18029023]
[149]
Jacobson KA, Klutz AM, Tosh DK, Ivanov AA, Preti D, Baraldi PG. Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering. In: PAdenosine Receptors in Health and Disease: Springer Berlin Heidelberg. 123-59. 2009; pp.
[150]
Kim H, Kang JW, Lee S, et al. A3 adenosine receptor antagonist, truncated Thio-Cl-IB-MECA, induces apoptosis in T24 human bladder cancer cells. Anticancer Res 2010; 30(7): 2823-30.
[PMID: 20683018]
[151]
Leung E. The use of adenosine A3 receptor antagonists to inhibit tumor growth. WO Patent 200001039: 2000.
[152]
Baraldi PG, Borea PA. Adenosine A3 receptor modulators. WO Patent 2003095457: 2003.
[153]
Borea PA, Leung E, Chen SF, Baraldi PG. Enhancing treatment of MDR cancer with adenosine A3 antagonists. WO Patent 2004000224: 2003.
[154]
Stemmer SM, Benjaminov O, Medalia G, et al. CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study. Oncologist 2013; 18(1): 25-6.
[http://dx.doi.org/10.1634/theoncologist.2012-0211] [PMID: 23299770]
[155]
Sachsenmeier K, Poon E, Sult E, Hay C. Therapeutic combinations comprising anti-CD73 antibodies and A2A receptor inhibitor and uses thereof. WO2016075176: 2016.
[156]
Chiappori A, Williams CC, Creelan BC, Tanvetyanon T, Gray JE, Haura EB. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC. J Clin Oncol 2018; 36: 9089.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.9089]
[157]
Fong L, Forde PM, Powderly JD, et al. Safety and clinical activity of adenosine A2A receptor (A2AR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients. J Clin Oncol 2017; 35: 3004.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.3004]
[158]
Hay CM, Sult E, Huang Q, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. OncoImmunology 2016; 5(8)e1208875
[http://dx.doi.org/10.1080/2162402X.2016.1208875] [PMID: 27622077]