Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells.
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 micromol/mL), NS-398 (100 micromol/mL), or indomethacin (20 micromol/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.
Bellosillo
B
B
Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet, Barcelona, Spain.
Piqué
M
M
Barragán
M
M
Castaño
E
E
Villamor
N
N
Colomer
D
D
Montserrat
E
E
Pons
G
G
Gil
J
J
D000368:Aged; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017302:Annexins / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D020910:Ketorolac; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D020156:Salicylic Acid; D013449:Sulfonamides / Q000494:pharmacology; D014046:Tolmetin / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D017302:Annexins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; D009578:Nitrobenzenes; D011506:Proteins; D012459:Salicylates; D013449:Sulfonamides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D014046:Tolmetin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D020156:Salicylic Acid; D001241:Aspirin; D007213:Indomethacin; D020910:Ketorolac