Deoxyadenosine- and cyclic AMP-induced cell cycle arrest and cytotoxicity.
We compared deoxyadenosine (AdR)- and cyclic AMP (cAMP)-induced cell cycle arrest and cytotoxicity in wild type and mutant S49 cells to determine whether they resulted from the same or different mechanisms. Cyclic AMP and deoxyadenosine are synergistic rather than additive in cytotoxicity assays, suggesting different mechanisms of toxicity. Although cyclic AMP causes cell death after 72 h, in concentrations sufficient to result in cell cycle arrest it is reversible with virtually no cytotoxicity for at least 24 h, whereas AdR-induced cell cycle arrest is lethal and irreversible. AdR-induced G1 cell cycle arrest results in diminished ribonucleotide reductase activity but the kinetics of this inhibition differ from cyclic AMP-induced cell cycle arrest. Cyclic AMP arrest and cytotoxicity depend on cyclic AMP-dependent protein kinase (PKA) activity, whereas AdR toxicity does not differ between cell lines with or without PKA activity. Furthermore, deoxycytidine prevents AdR cell cycle arrest and cytotoxicity but has no effect on cyclic AMP G1 arrest. Finally, comparison of cytofluorographic patterns of G1-arrested cells suggests that the AdR block is later in G1 than cyclic AMP-induced cell cycle arrest. In summary, these data show that while the mechanisms of cell cycle arrest and cytotoxicity of cyclic AMP and deoxyadenosine are uncertain, they do appear to involve different pathways.
Albert
D A
DA
Department of Medicine, University of Chicago Medical Center, Illinois 60637.
Nodzenski
E
E
Cruz
G H
GH
Kuchibholtla
J
J
Kowalski
J
J
D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death; D002455:Cell Division; D000242:Cyclic AMP / Q000633:toxicity*; D003839:Deoxyadenosines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003841:Deoxycytidine / Q000494:pharmacology; D004357:Drug Synergism; D007700:Kinetics; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D012333:RNA, Messenger; D003841:Deoxycytidine; D000242:Cyclic AMP; D012264:Ribonucleotide Reductases