B. Bellosillo et al., ASPIRIN AND SALICYLATE INDUCE APOPTOSIS AND ACTIVATION OF CASPASES INB-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA CELLS, Blood, 92(4), 1998, pp. 1406-1414
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.