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A Key Role for Caspase-2 and Caspase-3 in the Apoptosis Induced by 2-Chloro-2'-deoxy-adenosine (Cladribine) and 2-Chloro-adenosine in Human Astrocytoma Cells

Department of Pharmacological Sciences, School of Pharmacy (S.C., E.B., A.M., F.C., M.P.A.) and Center of Excellence for Neurodegenerative Diseases (S.C., F.C., M.P.A.), University of Milan, Milan, Italy; and Department of Ultrastructures, Istituto Superiore di Sanitá, Rome, Italy (P.M., W.M.)

Both the anticancer agent 2-chloro-2'-deoxy-adenosine (Cladribine) and its derivative 2-chloro-adenosine induce apoptosis of human astrocytoma cells (J Neurosci Res 60:388–400, 2000). In this study, we have analyzed the involvement of caspases in these effects. Both compounds produced a gradual and time-dependent activation of "effector" caspase-3, which preceded the appearance of the nuclear signs of apoptosis, suggesting a temporal correlation between these two events. Moreover, the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (fmk) suppressed both caspase-3 activation and apoptosis induction. "Initiator" caspase-9 and caspase-8 were only marginally activated at later times in the apoptotic process. Accordingly, at concentrations that selectively inhibit these caspases, neither N-benzyloxycarbonyl-Leu-Glu-His-Asp-fmk nor N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fmk could prevent adenosine analog-induced cell death. To definitively rule out a role for the caspase-9/cytochrome c-dependent mitochondrial pathway of cell death, neither adenosine analog had any effect on mitochondrial membrane potential, which was instead markedly reduced by other apoptotic stimuli (e.g., deoxyribose, NaCN, and betulinic acid). Consistently, although the latter triggered translocation of mitochondrial cytochrome c to the cytoplasm, no cytosolic accumulation of cytochrome c was detected with adenosine analogs. Conversely, 1 to 7 h after addition of either adenosine analog (i.e., before the appearance of caspase-3 activation), caspase-2 activity was surprisingly and markedly increased. The selective caspase-2 inhibitor N-benzyloxy carbonyl-Val-Asp-Val-Ala-Asp-fmk significantly reduced both adenosine analogs-induced caspase-2 activation and the associated cell death. We conclude that adenosine analogs induce the apoptosis of human astrocytoma cells by activating an atypical apoptotic cascade involving caspase-2 as an initiator caspase, and effector caspase-3. Therefore, these compounds could be effectively used in the pharmacological manipulation of tumors characterized by resistance to cell death via either the mitochondrial or caspase-8/death receptor pathways.

Received November 25, 2002; accepted March 14, 2003.

Address correspondence to: Prof. Maria P. Abbracchio-Department of Pharmacological Sciences, University of Milan and Center of Excellence for Neurodegenerative Diseases (CEND)-Via Balzaretti, 9-20133 Milan, Italy. E-mail: mariapia.abbracchio{at}unimi.it

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