Adenosine A(3) receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A(3) antagonists

The effects of novel, selective adenosine (ADO) A(3) receptor antagonists of diverse structure on cells of the human HL-60 leukemia and U-937 lymphoma cell lines were examined. Both 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine- 3,5-dicarboxylate (MRS 1191, 0.5 mu M) and 6-carboxymethyl-5,9-dihydro-9-methyl-2-phenyl-[1,2,4]-triazolo[5,1-a][2,7]naphthyridine (L-249313, 0.5 mu M) induced apoptotic cell death and expression of bak protein. Low concentrations of the A(3) receptor agonist 2-chloro-N-6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA, 10 nM or 1 mu M) protected against antagonist-induced cell death. At concentrations greater than or equal to 10 mu M, the agonist alone produced apoptosis and bak expression in various cell lines. It is suggested that there exists a tonic low level of A(3) receptor activation, possibly induced by release of endogenous adenosine, that results in cell protection. (C) 1997 Academic Press.