Pharmacological and therapeutic effects of A3 adenosine receptor agonists

Abstract

The A(3) adenosine receptor (A(3)AR) coupled to G(i) (inhibitory regulative guanine nucleotide-binding protein) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A(3)AR as a potential therapeutic target. Highly selective A(3)AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A(3)AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. At present, A(3)AR agonists are being developed for the treatment of inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.

Figure 1

Signaling pathways involved in the action of A₃AR agonists. Pathways proposed to be involved in anticancer, antiinflammatory, and cardioprotective effects of A₃AR agonists. A₃AR signals through both G protein-dependent (via G_i or β,γ subunits) and independent pathways. Translocation of arrestin to the A₃AR would be associated with receptor downregulation [22] and G protein-independent signaling. Not all pathways are present in all circumstances, and other pathways not shown can also affect cell survival, proliferation, and differentiation. In cancer (blue arrows), activation of the A₃AR corrects an imbalance in the downstream Wnt signaling pathway [6,34]. Administration of an A₃ agonist to activate its cell surface receptor inhibits the formation of cAMP and indirectly decreases phosphorylation (and therefore decreased inactivation) of the serine/threonine kinase GSK-3β. The resulting increased phosphorylation of β-catenin causes it to be removed from the cytoplasm by ubiquitination and therefore preventing its nuclear import. This results in a net suppression of cyclin D1 and c-myc, which leads to cell growth inhibition. With respect to cancer, NF-κB is a potent anti-apoptotic agent in malignant cells and its activation is strongly associated with tumors [76]. Additionally, as a major cell survival signal, NF-κB is involved in multiple steps in carcinogenesis and in cancer cells‘ resistance to chemo- and radiotherapy. Thus, drugs aimed to decrease expression or activity of NF-κB could abrogate its anti-apoptotic effect. In inflammatory models [7,8,9,20,29,71], the reduced activation of NF-κB (in synoviocytes, neutrophils, and other immune cells) has an antiinflammatory effect, in part by reducing the expression of TNF-α. Opposite effects of A3AR activation on some of these pathways (green arrows) are associated with myeloprotective (via increased NF-κB in splenocytes [39]) and cardioprotective (GSK-3β inhibition [47]) responses to A₃AR agonists. In the heart, there are opposing effects of GSK-3β at different stages of prolonged ischemia (GSK-3β protects) and reperfusion (GSK-3β inhibition protects) [77].

Figure 2

Representative agonists (1 – 8) and partial agonists (9, 10) of nanomolar affinity at the A₃AR and a positive allosteric modulator 11. Nucleosides 7 – 10 contain the (North) methanocarba substitution of the ribose ring, which maintains an A₃AR-preferred conformation.