Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells
Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells
复制标题
DOI：
10.1182/blood-2002-01-0075
复制
发表时间：
2003-01-01
期刊：
影响因子：
20.3
通讯作者：
Merle-Béral, H
中科院分区：
文献类型：
--
作者：
Sarfati, M;Mateo, V;Merle-Béral, H
据报道，4型磷酸二酯酶（PDE 4）抑制剂诱导慢性淋巴细胞白血病（CLL）细胞凋亡。在一例既往未接受过西地那非治疗的CLL患者临床改善后，我们评价了4种PDE 5/6抑制剂（包括西地那非、伐地那非、扎普司特和甲氧基喹唑啉（MQZ））对CLL细胞凋亡的体外诱导作用。培养24小时后，各种PDE抑制剂诱导细胞凋亡的能力不同，扎普司特没有显示出杀伤作用。从对照供体中分离的正常B细胞对PDE诱导的细胞凋亡具有完全抗性。伐地那非是3倍和30倍更有效的诱导细胞凋亡比西地那非和MQZ，分别。伐地那非和西地那非均未能升高腺苷3 '5'环磷酸（cAMP）水平，主要排除了对cAMP-PDE 3、-PDE 4和-PDE 7的抑制作用。伐地那非或昔地那非处理的BCLL细胞显示高达30%的细胞内活性半胱天冬酶3。药物诱导的细胞凋亡可被半胱天冬酶抑制剂z-VAD. f抑制，被白细胞介素-4（IL-4）阻止，并被基质衍生因子1-α（SDF-1 α）显著降低。我们得出结论，伐地那非和西地那非诱导半胱天冬酶依赖性凋亡的B-CLL细胞在体外，因此可能会被认为是在CLL患者的治疗。然而，应保证进一步的体内研究。(C)2003年，美国血液学会。
Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3'5' cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or slidenafil-treated BCLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-alpha (SDF-1alpha). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted. (C) 2003 by The American Society of Hematology.