APOPTOSIS INDUCED BY ADENOSINE IN HUMAN LEUKEMIA HL-60 CELLS

Among several nucleosides and nucleotides, which showed strong inhibition of growth of HL-60 cells, only adenosine (Ado) specifically induced typical apoptotic death of the cells, accompanying double-strand cleavage of DNA into nucleosomal size fragments, and subsequent apoptotic body formation. A marked enhancement of endogenous poly(ADP-ribosyl)ation activity in the cell was detected at a relatively early stage of cell death, whereas other nucleosides and nucleotides tested were ineffective on poly(ADP-ribosyl)ation activity, suggesting that the enzyme activation is closely related to apoptosis. The observed Ado effect was not mediated by Ado receptors, in contrast to the Ado-induced apoptotic death of thymocytes, judging from the facts that all of the receptor agonists tested did not substitute for Ado and that a receptor antagonist did not inhibit the effect of Ado. Ado transport into the cell seemed to be essential for the induction of apoptosis, since an inhibitor of Ado transport (dipyridamole) strongly suppressed apoptosis. Cytochalasin B blocked Ado-induced apoptotic body formation without affecting activation of endogenous poly(ADP-ribosyl)ation activity in the cell. Thus, the process of apoptosis in HL-60 cells induced by Ado seems to be separated into at least two steps, an initial step of DNA degradation and a following morphological change. While the adenine moiety of Ado was essential for its apoptosis-inducing activity, the sugar was replaceable, and various analogs with modified sugar were inducers of apoptosis, although they were less efficient than Ado. (C) 1994 Academic Press, Inc.