We previously demonstrated that both Cladribine (2-chloro-deoxyadenosine) and the related compound 2-chloroadenosine induce apoptosis of human astrocytoma cells (Ceruti et al.  J Neurosci Res 60:388-400). In the present study we have characterized the role of the most important "effector" caspase (caspase-3) in the same experimental model and the relationship between the intracellular phosphorylation of the two adenosine analogs and activation of this enzyme. Data show that: 1) both adenosine analogs can activate caspase-3 in a time-dependent fashion; 2) significant activation of the enzyme (i.e., 6-7-fold over control level) can be detected before any appearance of nuclear signs of apoptosis; 3) the degree of caspase-3 activation is proportional to the percentage of apoptosis at the end of the incubation period, suggesting a causal relationship between enzyme activation and induction of cell death; and 4) both activation of caspase-3 and induction of cell death can be completely prevented by preexposure of cultures to inhibitors of the intracellular phosphorylation of 2-chloroadenosine and 2-chloro-2'-deoxyadenosine (namely, 5-iodotubercidin and 2'-deoxycytidine, respectively). Adenosine analogs act, therefore, as prodrugs and the toxic species are represented by the corresponding chloro-nucleotides. The pathways upstream of caspase-3 activation in human astrocytoma cells still remain to be elucidated. Taken together, these data strongly suggest a possible use of adenosine analogs in the pharmacological treatment of central nervous system tumors and of all tumors characterized by a high activity of nucleoside kinases leading to selective intracellular accumulation of toxic chloro-nucleoticles.
Intracellular phosphorylation of chloro-adenosine analogs is a prerequisite for activation of caspase-3 and induction of apoptosis in human astrocytoma cells / S. Ceruti, A. Mazzola, E. Beltrami, D. Passera, E. Piantoni, F. Cattabeni, M.P. Abbracchio. - In: DRUG DEVELOPMENT RESEARCH. - ISSN 0272-4391. - 58:4(2003), pp. 396-404. ((Intervento presentato al 7. convegno International Symposium on Adenosine and Adenine Nucleotides tenutosi a Gold Coast nel 2002.
|Titolo:||Intracellular phosphorylation of chloro-adenosine analogs is a prerequisite for activation of caspase-3 and induction of apoptosis in human astrocytoma cells|
CERUTI, STEFANIA MARIA (Primo)
CATTABENI, FLAMINIO NICOLA (Penultimo)
ABBRACCHIO, MARIA PIA (Corresponding)
|Parole Chiave:||cell death; 2-chloro-adenosine; Cladribine; nucleotide kinases; central nervous system tumors|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2003|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/ddr.10184|
|Appare nelle tipologie:||01 - Articolo su periodico|