Bellosillo B, Piqué M, Barragán M, Castaño E, Villamor N, Colomer D, Montserrat E, Pons G, Gil J
Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet, Barcelona, Spain.
Blood. 1998 Aug 15;92(4):1406-14.
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.
我们分析了阿司匹林、水杨酸盐及其他非甾体抗炎药（NSAIDs）对B细胞慢性淋巴细胞白血病（B-CLL）细胞活力的影响。阿司匹林以剂量和时间依赖性方式诱导细胞活力下降。5例患者细胞的平均半数抑制浓度（IC50）为5.9±1.13 mmol/L（范围为4.4至7.3 mmol/L）。在某些情况下，2.5 mmol/L阿司匹林孵育4天后产生显著的细胞毒性作用。在抑制环氧化酶的浓度下，如酮咯酸（10 μmol/mL）、NS-398（100 μmol/mL）或吲哚美辛（20 μmol/mL），未观察到其他NSAIDs有此作用，这表明阿司匹林诱导的细胞毒性涉及不依赖环氧化酶的机制。水杨酸盐对B-CLL细胞也产生剂量依赖性细胞毒性作用，5例患者细胞的平均IC50为6.96±1.13 mmol/L（范围为5至7.8 mmol/L）。阿司匹林和水杨酸盐均诱导DNA片段化及聚（ADP（腺苷5'-二磷酸）-核糖）聚合酶（PARP）的蛋白水解切割，表明这两种化合物均诱导B-CLL细胞凋亡。最后，Z-VAD.fmk抑制半胱天冬酶可阻断PARP的蛋白水解切割、DNA片段化及阿司匹林诱导的细胞毒性。通过细胞活力分析确定，正常供体的单核细胞对阿司匹林的敏感性低于B-CLL患者的细胞。通过磷脂酰丝氨酸暴露分析确定，正常供体的B和T淋巴细胞以及CLL患者的T淋巴细胞对阿司匹林诱导的凋亡更具抗性。这些结果表明，阿司匹林和水杨酸盐通过激活半胱天冬酶诱导B-CLL细胞凋亡，且这种激活涉及不依赖环氧化酶的机制。
