Adenosine Receptors and Cancer

  • P. Fishman
  • S. Bar-Yehuda
  • M. Synowitz
  • J.D.  Powell
  • K.N. Klotz
  • S. Gessi
  • P.A. Borea
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 193)


The A1, A2A, A2B and A3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A1AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A1AR is mediated via tumor-associated microglial cells. Activation of the A2AAR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition of A2AAR activation by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A2BAR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A2BAR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A3AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A3AR transcription factor. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A3AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A3ARs that are abundantly expressed in tumor cells may be targeted by specific A3AR agonists, leading to tumor growth inhibition. The unique characteristics of these A3AR agonists make them attractive as drug candidates.


A1 adenosine receptor A2A adenosine receptor A2B adenosine receptor A3 adenosine receptor Expression Tumor growth Agonists Antagonists 



A1 adenosine receptor


A2A adenosine receptor


A2B adenosine receptor


A3 adenosine receptor


Antigen-presenting cells


Adenosine receptor


Basic fibroblast growth factor




Cluster of differentiation 39


Cluster of differentiation 73


Cancer Genome Anatomy Project


2-p-(2-Carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine 1680


Chinese hamster ovary cells

\(\mathrm{Cl}\! -\!\mathrm{IB} -\mathrm{MECA}\)



Central nervous system




Cytotoxic T lymphocyte-associated antigen 4


Cytotoxic T lymphocytes




Epidermal growth factor


Exchange protein activated by cAMP


Estrogen receptor


Extracellular signal-regulated kinase


Granulocyte colony stimulating factor


G-protein-coupled receptor


Glycogen synthase kinase 3β




Hepatocellular carcinoma


Hypoxia-inducible factor 1


High mobility group 1b


Human Genome Organization

\(\mathrm{IB}\rm{\textendash }\mathrm{MECA}\)

Methyl 1-[N6-(3-iodobenzyl)-adenin-9-yl]-β-d- ribofuronamid


IκB kinase




Lymphoid enhancer factor/T-cell factor


Mitogen-activated protein




3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-( ± )-dihydropyridine-3,5-dicarboxylate


1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan thiazolyl




Nuclear factor kappa B


Natural killers


Pathogen-associated molecular patterns


Poly(ADP-ribose) polymerase


Peripheral blood mononuclear cells


Pyrrolidine dithiocarbamate


Phosphoinositide 3-kinase


Protein kinase A


Protein kinase B


Protein kinase B/Akt


Phospholipase C


Phospholipase D


T-cell receptor


Transforming growth factor β

thio-\(\mathrm{Cl}\rm{\textendash }\mathrm{IB}\rm{\textendash }\mathrm{MECA}\)



Tumor necrosis factor


Vascular endothelial growth factor


Wild type


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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • P. Fishman
    • 1
  • S. Bar-Yehuda
    • 1
  • M. Synowitz
    • 2
  • J.D.  Powell
    • 3
  • K.N. Klotz
    • 4
  • S. Gessi
    • 5
  • P.A. Borea
    • 6
  1. 1.Can-Fite BioPharmaKiryat MatalonIsrael
  2. 2.Department of NeurosurgeryCharité-Universitätsmedizin BerlinBerlinGermany
  3. 3.The Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Universität Würzburg, Institut für Pharmakologie und ToxikologieWürzburgGermany
  5. 5.Department of Clinical and Experimental MedicineUniversity of FerraraFerraraItaly
  6. 6.Department of Clinical and Experimental MedicineUniversity of FerraraFerraraItaly

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