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Adenosine Receptors in Health and Disease pp 399–441Cite as

Adenosine Receptors and Cancer

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 193))

Abstract

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.

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Abbreviations

A1AR:

A1 adenosine receptor

A2AAR:

A2A adenosine receptor

A2BAR:

A2B adenosine receptor

A3AR:

A3 adenosine receptor

APCs:

Antigen-presenting cells

AR:

Adenosine receptor

bFGF:

Basic fibroblast growth factor

CCPA:

2-Chloro-N 6-cyclopentyladenosine

CD39:

Cluster of differentiation 39

CD73:

Cluster of differentiation 73

GGAP:

Cancer Genome Anatomy Project

CGS21680:

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

CHO:

Chinese hamster ovary cells

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

2-Chloro-N 6-3-iodobenzyladenosine-5′-N-methyluronamide

CNS:

Central nervous system

CPA:

N 6-Cyclopentyladenosine

CTLA-4:

Cytotoxic T lymphocyte-associated antigen 4

CTLs:

Cytotoxic T lymphocytes

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

EGF:

Epidermal growth factor

Epac:

Exchange protein activated by cAMP

ER:

Estrogen receptor

ERK:

Extracellular signal-regulated kinase

G-CSF:

Granulocyte colony stimulating factor

GPCR:

G-protein-coupled receptor

GSK-3β:

Glycogen synthase kinase 3β

HA:

Hyaluronan

HCC:

Hepatocellular carcinoma

HIF-1:

Hypoxia-inducible factor 1

HMG1b:

High mobility group 1b

HUGO:

Human Genome Organization

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

Methyl 1-[N 6-(3-iodobenzyl)-adenin-9-yl]-β-d- ribofuronamid

IKK:

IκB kinase

IL:

Interleukin

Lef/Tcf:

Lymphoid enhancer factor/T-cell factor

MAP:

Mitogen-activated protein

MMP:

Metalloproteinase

MRS1191:

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

MTT:

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

NECA:

Adenosine-5′-N-ethyluronamide

NF-κB:

Nuclear factor kappa B

NK:

Natural killers

PAMPs:

Pathogen-associated molecular patterns

PARP:

Poly(ADP-ribose) polymerase

PBMCs:

Peripheral blood mononuclear cells

PDTC:

Pyrrolidine dithiocarbamate

PI3K:

Phosphoinositide 3-kinase

PKA:

Protein kinase A

PKB:

Protein kinase B

PKB/Akt:

Protein kinase B/Akt

PLC:

Phospholipase C

PLD:

Phospholipase D

TCR:

T-cell receptor

TGF-β:

Transforming growth factor β

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

2-Chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide

TNF-α:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

Wt:

Wild type

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Authors and Affiliations

  1. Can-Fite BioPharma, 10 Bareket st., Kiryat Matalon, Petach Tikva, 49170, Israel

    P. Fishman & S. Bar-Yehuda

  2. Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    M. Synowitz

  3. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB I Building, Room 443, 1650 Orleans Street, Baltimore, MD, 21231, USA

    J.D. Powell

  4. Universität Würzburg, Institut für Pharmakologie und Toxikologie, Versbacher Str. 9, 97078, Würzburg, Germany

    K.N. Klotz

  5. Department of Clinical and Experimental Medicine, University of Ferrara, Pharmacology Unit Via Fossato di Mortara 17–19, 44100, Ferrara, Italy

    S. Gessi

  6. Department of Clinical and Experimental Medicine, University of Ferrara, Pharmacology Unit Via Fossato di Mortara 17-19, 44100, Ferrara, Italy

    P.A. Borea

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  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

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© 2009 Springer-Verlag Berlin Heidelberg

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Fishman, P. et al. (2009). Adenosine Receptors and Cancer. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_14

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