The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine.
2-chloroadenosine induced DNA fragmentation and cell death in human thymocytes primarily by Ca(2+)-dependent mechanisms. Incubation of human thymocytes with 2-chlorodeoxyadenosine (5-1000 nM) also induced cell death (apoptosis) which was dependent on macromolecule synthesis and involved activation of an endonuclease which was inhibited by Zn2+. The effect of 2-chlorodeoxyadenosine was prevented by addition of dipyridamole, a strong nucleoside transport inhibitor, or of deoxycytidine, previously shown to compete for uptake by deoxycytidine kinase. 2-Chlorodeoxyadenosine-induced apoptosis did not involve increases in the cytosolic Ca2+ concentration, but required the presence of intracellular Ca2+. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca(2+)-dependent cell death. Addition of 2-chlorodeoxyadenosine induced an increase in the amount of p53 in human thymocytes, while 2-chloroadenosine had no effect. These data suggest that 2-chloroadenosine and 2-chlorodeoxyadenosine induce cell death in human thymocytes via different signalling pathways.
D015762:2-Chloroadenosine / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D017338:Cladribine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology; D004720:Endonucleases / Q000378:metabolism; D006801:Humans; D007223:Infant; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D016159:Tumor Suppressor Protein p53; D015762:2-Chloroadenosine; D017338:Cladribine; D004176:Dipyridamole; D011493:Protein Kinase C; D004720:Endonucleases; D002118:Calcium