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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1406-1414
Aspirin and Salicylate Induce Apoptosis and Activation of Caspases in
B-Cell Chronic Lymphocytic Leukemia Cells
Beatriz Bellosillo,
Maria Piqué,
Montserrat Barragán,
Esther Castaño,
Neus Villamor,
Dolors Colomer,
Emilio Montserrat,
Gabriel Pons, and
Joan Gil
From the Departament de Ciències Fisiològiques II, Campus
de Bellvitge, Universitat de Barcelona, L'Hospitalet, Barcelona,
Spain; and the Unitat d'Hematopatologia and Servei d'Hematologia,
Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Hospital Clínic, Barcelona, Spain.
We analyzed the effect of aspirin, salicylate, and other
nonsteroidal antiinflammatory drugs (NSAIDs) on the viability of B-chronic lymphocytic leukemia (B-CLL) cells. Aspirin induced a
decrease in cell viability 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 after 4 days of incubation. No effect was
observed with other NSAIDs, at concentrations that inhibit
cyclooxygenase, such as ketorolac (10 µmol/mL), NS-398 (100 µmol/mL), or indomethacin (20 µmol/mL), thus suggesting the involvement of cyclooxygenase-independent mechanisms in aspirin-induced cytotoxicity. Salicylate also produced dose-dependent cytotoxic effects
on B-CLL cells and the mean IC50 for cells from 5 patients 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), demonstrating that both compounds induce apoptosis of B-CLL cells. Finally, inhibition of caspases by Z-VAD.fmk blocked proteolytic cleavage of PARP, DNA fragmentation, and cytotoxicity induced by
aspirin. Mononuclear 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 T lymphocytes from normal donors and
T lymphocytes from CLL patients are more resistant to aspirin-induced
apoptosis, as determined by analysis of phosphatidylserine exposure.
These results indicate that aspirin and salicylate induce apoptosis of
B-CLL cells by activation of caspases and that this activation involves
cyclooxygenase-independent mechanisms.
© 1998 by The American Society of Hematology.
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