SYNERGIC STIMULATION OF ARABINOSYLCYTOSINE INDUCED APOPTOSIS IN MOUSE THYMOCYTES BY CYCLIC-AMP

Previous studies demonstrated that arabinosylcytosine (ara-C) induced internucleosomal DNA fragmentation and cell death in mouse thymocytes and that those were inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine hydrochloride, an inhibitor of protein kinases. In the present study, we examined the relationship between the DNA fragmentation induced by ara-C and that by agents which activate intracellular signaling and induce apoptosis in mouse thymocytes. 12-O-tetradecanoyl 13-acetate, a phorbol ester capable of activating protein kinase C or A23187, a calcium ionophore, had no effect on ara-C induced DNA fragmentation. However, ara-C induced DNA fragmentation was synergistically enhanced by cAMP and cAMP receptor agonists. Ara-C inhibited the incorporation of choline into the acid soluble and lipid fractions, and cAMP enhanced this inhibition, suggesting that ara-C metabolites interfere with membrane phospholipid metabolism, partly evoking a certain cellular signaling for apoptosis and interacting with cAMP-evoked signaling.