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)

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.

Keywords

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

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-N6-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-N6-3-iodobenzyladenosine-5-N-methyluronamide

CNS

Central nervous system

CPA

N6-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-[N6-(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-N6-(3-iodobenzyl)-4-thioadenosine-5-N-methyluronamide

TNF-α

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

Wt

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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