Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists.
The effects of novel, selective adenosine (ADO) A3 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 microM) and 6-carboxy-methyl-5, 9-dihydro-9-methyl-2-phenyl-[1,2,4]-triazolo [5,1-a][2,7]naphthyridine (L-249313, 0.5 microM) induced apoptotic cell death and expression of bak protein. Low concentrations of the A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA, 10 nM or 1 microM) protected against antagonist-induced cell death. At concentrations > or = 10 microM, the agonist alone produced apoptosis and bak expression in various cell lines. It is suggested that there exists a tonic low level of A3 receptor activation, possibly induced by release of endogenous adenosine, that results in cell protection.
Yao
Y
Y
Laboratory of Bioorganic Chemistry, NIDDK/NIH, Bethesda, Maryland 20892, USA.
Sei
Y
Y
Abbracchio
M P
MP
Jiang
J L
JL
Kim
Y C
YC
Jacobson
K A
KA
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053938:DNA Fragmentation; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D004095:Dihydropyridines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011799:Quinazolines; D014230:Triazoles; C059017:AHC 52; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D000241:Adenosine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide