Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiological actions of adenosine. To date, four AR subtypes (adenosine A1, A2A, A2B and A3 receptors) have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. Among them, adenosine A3 receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. In addition, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury. It has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death. Furthermore, its mRNA and protein expression levels are upregulated in different tumor cell types (e.g., melanoma, prostate, colon, and hepatocellular carcinoma), but not in the adjacent normal tissues.
Namodenoson (also known as CF-102 or 2-Cl-IB-MECA), a ribose-based purine nucleoside, is a selective and orally active A3 adenosine receptor (A3AR) agonist.
Meanwhile, Namodenoson displays 2500- and 1400-fold selectivity for A3 over A1 and A2A receptors, respectively. Currently, Namodenoson has the potential for advanced liver cancer research. Mechanistically, Namodenoson involves the dysregulation of NF-κB and Wnt/β-catenin pathways, leading to tumor cell apoptosis. Besides, Namodenoson inhibits the growth of pancreatic adenocarcinoma in vitro and in vivo. In particular, Namodenoson inhibits BxPC-3 cell growth in a dose-dependent manner. In addition, Namodenoson modulates the expression of NF-κB, as well as proteins in the Wnt/β-catenin and the RAS signaling pathways, leading to the upregulation of apoptotic proteins (Bad, Bax). Moreover, Namodenoson enhances natural killer (NK) cell activity by inducing the production of IL-12. In vivo, Namodenoson (10 μg/kg; twice daily; for 35 days) significant inhibits the pancreatic carcinoma tumor growth in nude mice inoculated with BxPC-3 cells.
In summary, Namodenoson is a selective and orally active A3AR agonist with potent anticancer effects.
References:
[1] Inbal Itzhak, et al. Biomolecules. 2023 Oct 27;13(11):1584.
[2] E A Van Schaick, et al. Eur J Pharmacol. 1996 Jul 25;308(3):311-4.