Differential effect of adenosine on tumor and normal cell growth: Focus onthe A3 adenosine receptor

Adenosine is an ubiquitous nucleoside present in all body cells. It is rele ased from metabolically active or stressed cells and subsequently acts as a regulatory molecule through binding to specific A1, A(2A), A(2B) and A3 ce ll surface receptors. The synthesis of agonists and antagonists to the aden osine receptors and their cloning enabled the exploration of their physiolo gical functions. As nearly all cells express specific adenosine receptors, adenosine serves as a physiological regulator and acts as a cardioprotector , neuroprotector, chemoprotector, and as an immunomodulator. At the cellula r level, activation of the receptors by adenosine initiates signal transduc tion mechanisms through G-protein associated receptors. Adenosine's unique characteristic is to differentially modulate normal and transformed cell gr owth, depending upon its extracellular concentration, the expression of ade nosine cell surface receptors, and the physiological state of the target ce ll. Stimulation of cell proliferation following incubation with adenosine h as been demonstrated in a variety of normal cells in the range of low micro molar concentrations, including mesangial and thymocyte cells, Swiss mouse 3T3 fibroblasts, and bone marrow cells. Induction of apoptosis in tumor or normal cells was shown at higher adenosine concentrations (>100 muM) such a s in leukemia HL-60, lymphoma U-937, A431 epidermoid cells, and GH3 tumor p ituitary cell lines. It was further noted that the A3 adenosine receptor (A 3AR) plays a key role in the inhibitory and stimulatory growth activities o f adenosine. Modulation of the A3AR was found to affect cell growth either positively or negatively depending on the concentration of the agonist, sim ilar to the effect described for adenosine. At nanomolar concentrations, th e A3AR agonists possess dual activity, i.e., antiproliferative activity tow ard tumor cells and stimulatory effect on bone marrow cells. In vivo, these agonists exerted anti-cancer effects, and when given in combination with c hemotherapy, they enhanced the chemotherapeutic index and acted as chemopro tective agents. Taken together, activation of the A3AR, by minute concentra tions of its natural ligand or synthetic agonists, may serve as a new appro ach for cancer therapy. J. Cell. Physiol. 186:19-23, 2001. (C) 2001 Wiley-L iss, Inc.