Adenosine receptors and cancer

Abstract

Adenosine is a ubiquitous signaling molecule whose physiological functions are mediated by its interaction with four G-protein-coupled receptor subtypes, termed A(1), A(2A), A(2B) and A(3). As a result of increased metabolic rates, this nucleoside is released from a variety of cells throughout the body in concentrations that can have a profound impact on vasculature and immunoescape. However, as high concentrations of adenosine have been reported in cancer tissues, it also appears to be implicated in the growth of tumors. Thus, full characterisation of the role of adenosine in tumor development, by addressing the question of whether adenosine receptors are present in cancer tissues, and, if so, which receptor subtype mediates its effects in cancer growth, is a vital research goal. To this end, this review focuses on the most relevant aspects of adenosine receptor subtype activation in tumors reported so far. Although all adenosine receptors now have an increasing number of recognised biological roles in tumors, it seems that the A(2A) and A(3) subtypes are the most promising as regards drug development. In particular, activation of A(2A) receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth. Due to this behavior, the addition of A(2A) antagonists to cancer immunotherapeutic protocols has been suggested as a way of enhancing tumor immunotherapy. Interestingly, the safety of such compounds has already been demonstrated in trials employing A(2A) antagonists in the treatment of Parkinson's disease. As for A(3) receptors, the effectiveness of their agonists in several animal tumor models has led to the introduction of these molecules into a programme of pre-clinical and clinical trials. Paradoxically, A(3) receptor antagonists also appear to be promising candidates in human cancer treatment of regimes. Clearly, research in this still field is still in its infancy, with several important and challenging issues remaining to be addressed, although purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.

Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

“…1B and 7C), together with data on predominant expression of the A 2B receptors on PC-3 and MDA-MB-231 cells (refs. 26, 28; also present study), and diverse pro-and antitumoral roles of A 2B receptors in different tumors (13,26), may also indicate the involvement of A 2B -receptor-mediated signaling in control of tumor invasion, growth and proliferation, especially at high micromolar concentrations of agonist. The array signals from scanned X-ray film images from two independent experiments are shown.…”

“…Current research on the role of adenosine in tumor pathogenesis and inflammation is particularly focused on targeting the releasing pathways of the precursor nucleotide ATP (7,34), directional regulation of ecto-5 0 -nucleotidase/ CD73 activity by using selective enzyme inhibitors, siRNA gene silencing and anti-CD73 mAb therapies (10,12,32), synthesis of phosphorylated adenosine derivatives acting as site-specific CD73-activated prodrugs of A 2A receptors (40), as well as development of nonmetabolizable nucleoside analogues acting either as selective adenosine receptor agonists and antagonists (5,13) or as metabolic inhibitors of intracellular purine homeostasis (16,20). Yet another approach includes tumor treatment with adenosine as a "kindred" metabolite; however, most of the proapoptotic and antiproliferative effects of adenosine reported in studies with different malignant cells required continuous presence of supra-physiological nucleoside concentrations (0.1-20 mmol/L) in the assay mixture (15,(17)(18)(19).…”

“…9) and ecto-5 0 -nucleotidase/CD73 (4,(10)(11)(12). High activities of ecto-5 0 -nucleotidase/CD73 and other nucleotidases may contribute to the clearance of proinflammatory and proangiogenic ATP in the tumor environment (4,7,9), simultaneously leading to A 2A adenosine receptormediated inhibition of effector immune cells, including cytotoxic T-lymphocytes, natural killer cells, dendritic cells, and macrophages (3,13,14).…”

Adenosine A2A and A2B receptor expression in neuroendocrine tumours: potential targets for therapy

“…Adenosine mediates its actions through four adenosine receptors, A 1 , A 2A , A 2B and A 3 , which are differentially expressed in different tissues [12]. Therapeutic modulation of adenosine levels or signalling could therefore provide a basis for the treatment of many cancers [13][14][15]. In this study, we show that A 2A and A 2B receptors are the dominant adenosine receptors in human NET cell lines and in archival human NET tissue.…”

“…RNA (0.2 μg) was reverse transcribed using oligodeoxythymidilic acid [oligo(dT) 15 ] for 1 h at 37°C and the cDNA generated was subjected to PCR amplification using primers specific for human adenosine receptors. Primer sequences (shown in Table 1) were designed using the Primer 3 software programme and gene sequences obtained from GenBank.…”