title: A3 adenosine receptor agonist potentiates natural killer cell activity.
abstract: Activation of the Gi-protein-coupled A3 adenosine receptor (A3AR) has been reported to be involved in the inhibition of tumor cell growth. A3AR is highly expressed in tumor cells whereas lower expression was noted in a variety of normal cells. Recently we showed that A3AR activation in melanoma cells resulted in growth inhibition via a direct anti-proliferative effect which entailed cell cycle arrest in the G0/G1 and down-regulation of cyclin D1 and c-Myc. In the present study we present an additional mechanism demonstrating that A3AR agonists activate natural killer (NK) cells which further enhance the anti-tumor effect of this group of molecules. NK cells mediate the natural cytotoxicity and their number and function is reduced in cancer patients. We show Cl-IB-MECA to inhibit tumor development via the activation of NK cells is an additional mechanism which accounts for the anti-tumor effect of A3AR agonists. This effect was noted at a low dose of 10 micro g/kg, demonstrating that the response is exclusively A3AR mediated. Treatment of naïve mice for four days yielded the highest effect on NK cell potentiation. In mice inoculated with B16-F10 melanoma cells and treated each orally with Cl-IB-MECA, melanoma growth inhibition correlated with higher serum level of IL-12 and potentiation of NK cells. Moreover, in adoptive transfer experiments in melanoma bearing mice, marked inhibition of lung metastatic foci was noted upon engraftment with splenocytes derived from Cl-IB-MECA treated mice. Taken together, the ability of Cl-IB-MECA to inhibit tumor development via the activation of NK cells is an additional mechanism which accounts for the anti-tumor effect of A3AR agonists.
authors.affiliation: Department of Surgery A/B and Pathology, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine, Tel-Aviv University, Petach-Tikva 49100, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Harish
authors.forename: Gil
authors.initials: G
authors.lastname: Hohana
authors.forename: Pnina
authors.initials: P
authors.lastname: Fishman
authors.forename: Oshra
authors.initials: O
authors.lastname: Arnon
authors.forename: Sara
authors.initials: S
authors.lastname: Bar-Yehuda
mesh_terms: D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle; D013154:Spleen / Q000166:cytology
chemical_list: D058909:Adenosine A3 Receptor Agonists; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D018664:Interleukin-12