Agonists and antagonists: Molecular mechanisms and therapeutic applications

The possibility that A3 adenosine receptor plays a role in the development of cancer has aroused considerable interest in recent years. The A3AR is over-expressed in several cancer cell lines, in cancer tissues and in the peripheral blood mononuclear cells (PBMC) of patients with colorectal cancer. Due to the complex and enigmatic role of the A3 receptor evidences have been reported that both agonist and antagonists may be useful for cancer treatment. In this chapter, the anti-cancer effect of highly selective agonists to the A3 adenosine receptor (A3AR) is presented. A3AR over-expression is a characteristic of various tumor cell types and synthetic agonists such as IB-MECA, Cl-IB-MECA and thio-Cl-IB-MECA which target the receptor with high affinity and selectivity, inhibit in vitro the proliferation of leukemia, lymphoma and solid tumor cell lines. A3AR agonists given via an oral route, suppress the growth of melanoma, colon, breast, prostate and hepatocellular carcinoma (HCC) in syngeneic and xenograf murine models. Upon chronic treatment of the animals with a given agonist, receptor tachyphylaxis did not occur, supporting the notion that A3AR is a valid target. Mechanistically, A3AR agonists induce direct effect on tumor cell growth manifested by de-regulation of the nuclear factor κB (NF-κB) and the Wnt signal transduction pathways, resulting in cell cycle arrest and apoptosis. Moreover, A 3AR agonists induce an immunomodulatory effect via the inhibition of interleukin-12 production and activation of natural killer cells. Efficacy of Cl-IB-MECA in several animal models of cancer, coupled with its safety profile, suggest this compound as a reasonable candidate for development in cancerous diseases, including HCC. Furthermore in this chapter also the potential role of antagonists with particular mention of the role of hypoxia in tumors, adenosine in hypoxia, HIF-1α in hypoxic tumors and A3 regulation of HIF-1α and angiogenesis is described. A potential role for A3 antagonists has also been hypothesized in immunotherapies of cancer.