Adenosine Receptors and Current Opportunities to Treat Cancer

  • Stefania Gessi
  • Stefania MerighiEmail author
  • Pier Andrea Borea
  • Shira Cohen
  • Pnina Fishman
Part of the The Receptors book series (REC, volume 34)


Adenosine is an endogenous modulator exerting its physiological effects by activating four A1, A2A, A2B, and A3 adenosine receptors. This nucleoside increases in hypoxia that characterizes solid tumors, thus affecting vasculature, immunoescaping, and cancer growth. This chapter offers an updated overview on the current opportunities to treat tumors coming from the adenosinergic field. Several years of research has led to the conclusion that A2A and A3 subtypes are the most promising for drug development. As for A3 receptors, consequent to the efficacy of their agonists in numerous animal models of cancer, the lead compound, Namodenoson, has entered in clinical trials for hepatocellular carcinoma. Phase I results proved its optimal safety profile and efficacy, so that phase II studies are in progress. Specifically, A2A receptor is responsible for immunosuppressive effects, reducing antitumor immunity and promoting immunoescaping of cancer. Therefore, A2A receptor antagonists have been proposed to fight cancer by enhancing immunotherapy, supported also by their safety already demonstrated in clinical trials for Parkinson’s disease. Overall, from these positive results, it may be expected that A3 agonists and A2A antagonists may become future anticancer drugs with the ability to save and improve human health also for diseases with very limited treatment options.


A2A receptors A3 receptor Cell proliferation Immunoescaping Immunoprotection Clinical trials 


  1. Aghaei M, Panjehpour M, Karami-Tehrani F, Salami S (2011) Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway. J Cancer Res Clin Oncol 137:1511–1523CrossRefPubMedGoogle Scholar
  2. Allard D, Allard B, Gaudreau P-O et al (2016) CD73-adenosine: a next-generation target in immuno-oncology. Immunotherapy 8:145–163CrossRefPubMedGoogle Scholar
  3. Antonioli L, Csóka B, Fornai M et al (2014) Adenosine and inflammation: what’s new on the horizon? Drug Discov Today 19:1051–1068CrossRefPubMedGoogle Scholar
  4. Bao R, Shui X, Hou J et al (2016) Adenosine and the adenosine A2A receptor agonist, CGS21680, upregulate CD39 and CD73 expression through E2F-1 and CREB in regulatory T cells isolated from septic mice. Int J Mol Med 38:969–975CrossRefPubMedGoogle Scholar
  5. Bar-Yehuda S, Farbstein T, Barer F et al (1999) Oral administration of muscle derived small molecules inhibits tumor spread while promoting normal cell growth in mice. Clin Exp Metastasis 17:531–535CrossRefPubMedGoogle Scholar
  6. Bar-Yehuda S, Barer F, Volfsson L, Fishman P (2001) Resistance of muscle to tumor metastases: a role for a3 adenosine receptor agonists. Neoplasia 3:125–131CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bar-Yehuda S, Madi L, Barak D et al (2002) Agonists to the A3 adenosine receptor induce G-CSF production via NF-k B activation: a new class of myeloprotective agents. Exp Hematol 30:1390–1398CrossRefPubMedGoogle Scholar
  8. Bar-Yehuda S, Madi L, Silberman D et al (2005) CF101, an agonist to the a 3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a Colon carcinoma murine model. Neoplasia 7:85–90CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bar-Yehuda S, Stemmer SM, Madi L et al (2008) 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 33:287–295PubMedGoogle Scholar
  10. Beavis PA, Divisekera U, Paget C et al (2013) Blockade of A2A receptors potently suppresses the metastasis of CD73 + tumors. Proc Natl Acad Sci 110:14711–14716CrossRefPubMedGoogle Scholar
  11. Beavis PA, Milenkovski N, Henderson MA et al (2015) Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res 3:506–517CrossRefPubMedGoogle Scholar
  12. Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57:2602–2605PubMedGoogle Scholar
  13. Borea PA, Gessi S, Merighi S, Varani K (2016) Adenosine as a multi-Signalling Guardian angel in human diseases: when, where and how does it exert its protective effects? Trends Pharmacol Sci 37:419–434CrossRefPubMedGoogle Scholar
  14. Borea PA, Gessi S, Merighi S et al (2017) Pathological overproduction: the bad side of adenosine. Br J Pharmacol 174:1945–1960CrossRefPubMedGoogle Scholar
  15. Bruzzese L, Fromonot J, By Y et al (2014) NF-κB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A2A receptors. Cell Signal 26:1060–1067CrossRefPubMedGoogle Scholar
  16. Carpenter B, Nehmé R, Warne T et al (2016) Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 536:104–107CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cohen S, Stemmer SM, Zozulya G et al (2011) CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol 226:2438–2447CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fishman P, Bar-Yehuda S, Vagman L (1998) Adenosine and other low molecular weight factors released by muscle cells inhibit tumor cell growth. Cancer Res 58:3181–3187PubMedGoogle Scholar
  19. Fishman P, Bar-Yehuda S, Farbstein T et al (2000a) Adenosine acts as a Chemoprotective agent by stimulating G-CSF production: a role for A1 and A3 adenosine receptors. J Cell Physiol 183:393–398CrossRefPubMedGoogle Scholar
  20. Fishman P, Bar-Yehuda S, Ohana G et al (2000b) Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the A3 adenosine receptor. Eur J Cancer 36:1452–1458CrossRefPubMedGoogle Scholar
  21. Fishman P, Bar-Yehuda S, Barer F et al (2001) The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 269:230–236CrossRefPubMedGoogle Scholar
  22. Fishman P, Bar-Yehuda S, Madi L, Cohn I (2002a) A3 adenosine receptor as a target for cancer therapy. Anti-Cancer Drugs 13:437–443CrossRefPubMedGoogle Scholar
  23. Fishman P, Madi L, Bar-Yehuda S et al (2002b) Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 21:4060–4064CrossRefPubMedGoogle Scholar
  24. Fishman P, Bar-Yehuda S, Ardon E et al (2003) Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist. Anticancer Res 23:2077–2083PubMedGoogle Scholar
  25. Fishman P, Bar-Yehuda S, Ohana G et al (2004) An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3 beta and NF-kappa B. Oncogene 23:2465–2471CrossRefPubMedGoogle Scholar
  26. Fishman P, Bar-Yehuda S, Synowitz M, et al (2009) Adenosine receptors and cancer. Handb Exp Pharmacol 193:399–441. Wilson CN, Mustafa SJ (ed)Google Scholar
  27. Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA (2012) Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359–366CrossRefPubMedGoogle Scholar
  28. Gessi S, Varani K, Merighi S et al (2001) Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells. Br J Pharmacol 134:116–126CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gessi S, Varani K, Merighi S et al (2002) A(3) adenosine receptors in human neutrophils and promyelocytic HL60 cells: a pharmacological and biochemical study. Mol Pharmacol 61:415–424CrossRefPubMedGoogle Scholar
  30. Gessi S, Cattabriga E, Avitabile A et al (2004) Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res 10:5895–5901CrossRefPubMedGoogle Scholar
  31. Gessi S, Merighi S, Varani K et al (2007) Adenosine receptors in colon carcinoma tissues and colon tumoral cell lines: focus on the a(3) adenosine subtype. J Cell Physiol 211:826–836CrossRefPubMedGoogle Scholar
  32. Gessi S, Merighi S, Varani K et al (2008) The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140CrossRefPubMedGoogle Scholar
  33. Gessi S, Fogli E, Sacchetto V et al (2010a) Adenosine modulates HIF-1alpha, VEGF, IL-8, and foam cell formation in a human model of hypoxic foam cells. Arterioscler Thromb Vasc Biol 30:90–97CrossRefPubMedGoogle Scholar
  34. Gessi S, Sacchetto V, Fogli E et al (2010b) Modulation of metalloproteinase-9 in U87MG glioblastoma cells by A3 adenosine receptors. Biochem Pharmacol 79:1483–1495CrossRefPubMedGoogle Scholar
  35. Gessi S, Merighi S, Sacchetto V et al (2011) Adenosine receptors and cancer. Biochim Biophys Acta Biomembr 1808:1400–1412CrossRefGoogle Scholar
  36. Harish A, Hohana G, Fishman P et al (2003) A3 adenosine receptor agonist potentiates natural killer cell activity. Int J Oncol 23:1245–1249PubMedGoogle Scholar
  37. Hatfield SM, Sitkovsky M (2016) A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol 29:90–96CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hofer M, Pospíšil M, Vacek A et al (2006) Effects of adenosine A3 receptor agonist on bone marrow granulocytic system in 5-fluorouracil-treated mice. Eur J Pharmacol 538:163–167CrossRefPubMedGoogle Scholar
  39. Huang S, Apasov S, Koshiba M, Sitkovsky M (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90:1600–1610PubMedGoogle Scholar
  40. Iannone R, Miele L, Maiolino P et al (2013) Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 15:1400–1409CrossRefPubMedPubMedCentralGoogle Scholar
  41. Jacobson KA, Merighi S, Varani K et al (2017) A3 adenosine receptors as modulators of inflammation: from medicinal chemistry to therapy. Med Res Rev.
  42. Jajoo S, Mukherjea D, Watabe K, Ramkumar V (2009) Adenosine a(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 11:1132–1145CrossRefPubMedPubMedCentralGoogle Scholar
  43. Jazayeri A, Andrews SP, Marshall FH (2017) Structurally enabled discovery of adenosine A2A receptor antagonists. Chem Rev 117:21–37CrossRefPubMedGoogle Scholar
  44. Jin D, Fan J, Wang L et al (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 70:2245–2255CrossRefPubMedPubMedCentralGoogle Scholar
  45. Khoa ND, Montesinos MC, Reiss AB et al (2001) Inflammatory cytokines regulate function and expression of adenosine a(2A) receptors in human monocytic THP-1 cells. J Immunol 167:4026–4032CrossRefPubMedGoogle Scholar
  46. Koshiba M, Kojima H, Huang S et al (1997) Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 272:25881–25889CrossRefPubMedGoogle Scholar
  47. Lappas CM, Rieger JM, Linden J (2005a) A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073–1080CrossRefPubMedGoogle Scholar
  48. Lappas CM, Sullivan GW, Linden J (2005b) Adenosine a 2A agonists in development for the treatment of inflammation. Expert Opin Investig Drugs 14:797–806CrossRefPubMedGoogle Scholar
  49. Loi S, Pommey S, Haibe-Kains B et al (2013) CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci U S A 110:11091–11096CrossRefPubMedPubMedCentralGoogle Scholar
  50. Lukashev D, Ohta A, Sitkovsky M (2007a) Hypoxia-dependent anti-inflammatory pathways in protection of cancerous tissues. Cancer Metastasis Rev 26:273–279CrossRefPubMedGoogle Scholar
  51. Lukashev D, Sitkovsky M, Ohta A (2007b) From ‘Hellstrom paradox–to anti-adenosinergic cancer immunotherapy. Purinergic Signal 3:129–134CrossRefPubMedPubMedCentralGoogle Scholar
  52. Ma S-R, Deng W-W, Liu J-F et al (2017) Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma. Mol Cancer 16:99CrossRefPubMedPubMedCentralGoogle Scholar
  53. Madi L, Bar-Yehuda S, Barer F et al (2003) A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. J Biol Chem 278:42121–42130CrossRefPubMedGoogle Scholar
  54. Madi L, Ochaion A, Rath-Wolfson L et al (2004) The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin Cancer Res 10:4472–4479CrossRefPubMedGoogle Scholar
  55. Maj T, Wang W, Crespo J et al (2017) Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18:1332–1341CrossRefPubMedPubMedCentralGoogle Scholar
  56. Mediavilla-Varela M, Luddy K, Noyes D et al (2013) Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol Ther 14:860–868CrossRefPubMedPubMedCentralGoogle Scholar
  57. Mediavilla-Varela M, Castro J, Chiappori A et al (2017) A novel antagonist of the immune checkpoint protein adenosine A2a receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment. Neoplasia 19:530–536CrossRefPubMedPubMedCentralGoogle Scholar
  58. Merighi S, Varani K, Gessi S et al (2001) Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line. Br J Pharmacol 134:1215–1226CrossRefPubMedPubMedCentralGoogle Scholar
  59. Merighi S, Mirandola P, Varani K et al (2003) A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 100:31–48CrossRefPubMedGoogle Scholar
  60. Merighi S, Benini A, Mirandola P et al (2005) 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 280:19516–19526CrossRefPubMedGoogle Scholar
  61. Merighi S, Benini A, Mirandola P et al (2006) Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol 72:19–31CrossRefPubMedGoogle Scholar
  62. Merimsky O, Bar-Yehuda S, Madi L, Fishman P (2003) Modulation of the A3 adenosine receptor by low agonist concentration induces antitumor and Myelostimulatory effects. Drug Dev 58:386–389CrossRefGoogle Scholar
  63. Montinaro A, Forte G, Sorrentino R et al (2012) Adoptive immunotherapy with cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice. PLoS One 7:e45401CrossRefPubMedPubMedCentralGoogle Scholar
  64. Morello S, Petrella A, Festa M et al (2008) Cl-IB-MECA inhibits human thyroid cancer cell proliferation independently of A3 adenosine receptor activation. Cancer Biol Ther 7:278–284CrossRefPubMedGoogle Scholar
  65. Morello S, Sorrentino R, Porta A et al (2009) Cl-IB-MECA enhances TRAIL-induced apoptosis via the modulation of NF-kappaB signalling pathway in thyroid cancer cells. J Cell Physiol 221:378–386CrossRefPubMedGoogle Scholar
  66. Naganuma M, Wiznerowicz EB, Lappas CM et al (2006) Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol 177:2765–2769CrossRefPubMedGoogle Scholar
  67. Ohana G, Bar-Yehuda S, Barer F, Fishman P (2001) Differential effect of adenosine on tumor and normal cell growth: focus on the A3 adenosine receptor. J Cell Physiol J Cell Physiol 186:19–2319CrossRefPubMedGoogle Scholar
  68. Ohana G, Bar-Yehuda S, Arich A et al (2003) Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101. Br J Cancer 89:1552–1558CrossRefPubMedPubMedCentralGoogle Scholar
  69. Ohta A (2016) A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol 7:109CrossRefPubMedPubMedCentralGoogle Scholar
  70. Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920CrossRefPubMedGoogle Scholar
  71. Ohta A, Gorelik E, Prasad SJ et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci 103:13132–13137CrossRefPubMedGoogle Scholar
  72. Pardoll D (2002) T cells take aim at cancer. Proc Natl Acad Sci 99:15840–15842CrossRefPubMedGoogle Scholar
  73. Raskovalova T, Lokshin A, Huang X et al (2007) Inhibition of cytokine production and cytotoxic activity of human Antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase a type I signaling. Cancer Res 67:5949–5956CrossRefPubMedGoogle Scholar
  74. Ryzhov S, Novitskiy SV, Zaynagetdinov R et al (2008) Host a(2B) adenosine receptors promote carcinoma growth. Neoplasia 10:987–995CrossRefPubMedPubMedCentralGoogle Scholar
  75. Schnurr M, Toy T, Shin A et al (2003) Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood 103:1391–1397CrossRefPubMedGoogle Scholar
  76. Serra S, Vaisitti T, Audrito V et al (2016) Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment. Blood Adv 1:47–61CrossRefPubMedPubMedCentralGoogle Scholar
  77. Sitkovsky MV (2003) Use of the a(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo. Biochem Pharmacol 65:493–501CrossRefPubMedGoogle Scholar
  78. Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30:102–108CrossRefPubMedGoogle Scholar
  79. Sitkovsky MV, Lukashev D, Apasov S et al (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia -inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682CrossRefPubMedGoogle Scholar
  80. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14:5947–5952CrossRefPubMedGoogle Scholar
  81. Stemmer SM, Benjaminov O, Medalia G et al (2013) CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study. Oncologist 18:25–26CrossRefPubMedPubMedCentralGoogle Scholar
  82. Torgersen KM, Vang T, Abrahamsen H et al (2002) Molecular mechanisms for protein kinase A-mediated modulation of immune function. Cell Signal 14:1–9CrossRefPubMedGoogle Scholar
  83. Van Troostenburg A-R, Clark EV, Carey WDH et al (2004) Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther 42:534–542CrossRefPubMedGoogle Scholar
  84. Varani K, Maniero S, Vincenzi F et al (2011) A3 receptors are overexpressed in pleura from patients with mesothelioma and reduce cell growth via Akt/nuclear factor-κB pathway. Am J Respir Crit Care Med 183:522–530CrossRefPubMedGoogle Scholar
  85. Varani K, Vincenzi F, Targa M et al (2013) The stimulation of a(3) adenosine receptors reduces bone-residing breast cancer in a rat preclinical model. Eur J Cancer 49:482–491CrossRefPubMedGoogle Scholar
  86. Vincenzi F, Targa M, Corciulo C et al (2012) The anti-tumor effect of A3 adenosine receptors is potentiated by pulsed electromagnetic fields in cultured neural cancer cells. PLoS One 7:e39317CrossRefPubMedPubMedCentralGoogle Scholar
  87. Yuan G, Jankins TC, Patrick CG et al (2017) Fluorinated adenosine a 2A receptor antagonists inspired by Preladenant as potential Cancer Immunotherapeutics. Int J Med Chem 2017:1–8Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Stefania Gessi
    • 1
  • Stefania Merighi
    • 1
    Email author
  • Pier Andrea Borea
    • 1
  • Shira Cohen
    • 2
  • Pnina Fishman
    • 2
  1. 1.Department of Medical SciencesUniversity of FerraraFerraraItaly
  2. 2.Can Fite BiopharmaPetah-TikvaIsrael

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