Apoptosis induced by 2-chloro-adenosine and 2-chloro-2 '-deoxy-adenosine in a human astrocytoma cell line: Differential mechanisms and possible clinical relevance

We have previously demonstrated that il-chloro-adenosine (2-CA) can induce apoptosis of rat astroglial cells (Abbracchio et al, [1995] Biochem. Biophy s, Res. Commun, 213, 908-915), In the present study, we have characterized, for the first time, the effects induced on a human astrocytoma cell line ( ADF cells) by both 2-CA and its related analog 2-chloro-2'-deoxy-adenosine (2-CdA, that is employed as anti-cancer agent in chronic lymphoid malignanc ies). Exposure of these cells to either adenosine analog resulted in time- and concentration-dependent apoptosis. Experiments with pharmacological age nts known to interfere with adenosine receptors, its membrane transporter, and intracellular nucleoside kinases showed that: (i) cell death induced by either adenosine analog did not depend on extracellular adenosine receptor s, but on a direct intracellular action; however, only in the case of 2-CA, was entry into cells mediated by the specific nitrobenzyl-tioinosine-sensi tive transporter; (ii) for both adenosine analogs, induction of apoptosis r equired the phosphorylation/activation by specific intracellular nucleoside kinases, i.e., adenosine kinase for 2-CA, and deoxycytidine kinase for 2-C dA. In addition, only in the case of 2-CdA, was induction of apoptosis prec eded by a block of cells at the G2/M phase of the cell cycle. Finally, at c oncentrations of either analog that killed about 80-90% of astrocytoma cell s, a significantly lower effect on the viability of primary cortical neuron s was observed. In conclusion, both adenosine analogs can trigger apoptosis of human astrocytoma cells, albeit with different mechanisms. This effect together with the relative sparing of neuronal cells, may have potential cl inical implications for the therapy of tumors of glial origin. (C) 2000 Wil ey-Liss, Inc.