ASPIRIN AND SALICYLATE INDUCE APOPTOSIS AND ACTIVATION OF CASPASES INB-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA CELLS

We analyzed the effect of aspirin, salicylate, and other nonsteroidal antiinflammatory drugs (NSAIDs) on the viability of B-chronic lymphocy tic leukemia (B-CLL) cells. Aspirin induced a decrease in cell viabili ty in a dose- and time-dependent manner. The mean IC50 for cells from 5 patients was 5.9 +/- 1.13 mmol/L (range, 4.4 to 7.3 mmol/L). in some cases, 2.5 mmol/L aspirin produced an important cytotoxic effect afte r 4 days of incubation. Mo effect was observed with other NSAIDs, at c oncentrations that inhibit cyclooxygenase, such as ketorolac (10 mu mo l/mL), NS-398 (100 mu mol/mL), or indomethacin (20 mu mol/mL), thus su ggesting the involvement of cyclooxygenase-independent mechanisms in a spirin-induced cytotoxicity. Salicylate also produced dose-dependent c ytotoxic effects on B-CLL cells and the mean IC50 for cells from 5 pat ients was 6.96 +/- 1.13 mmol/L (range, 5 to 7.8 mmol/L). Both aspirin and salicylate induced DNA fragmentation and the proteolytic cleavage of poly(ADP(adenosine 5'-diphosphate)-ribose) polymerase (PARP), demon strating that both compounds induce apoptosis of B-CLL cells. Finally, inhibition of caspases by Z-VAD.fmk blocked proteolytic cleavage of P ARP, DNA fragmentation, and cytotoxicity induced by aspirin. Mononucle ar cells from normal donors showed a lower sensitivity than cells from B-CLL patients to aspirin as determined by analysis of cell viability . B and a lymphocytes from normal donors and T lymphocytes from CLL pa tients are more resistant to aspirin-induced apoptosis, as determined by analysis of phosphatidylserine exposure. These results indicate tha t aspirin and salicylate induce apoptosis of B-CLL cells by activation of caspases and that this activation involves cyclooxygenase-independ ent mechanisms. (C) 1998 by The American Society of Hematology.