Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of caspases
Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of caspases
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DOI：
10.1007/bf02787360
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发表时间：
1999-04-01
期刊：
影响因子：
3.4
通讯作者：
Gallagher, RE
中科院分区：
文献类型：
--
作者：
Huang, XJ;Wiernik, PH;Gallagher, RE
本研究的主要目的是确定半胱天冬酶是否参与三氧化二砷（ATO）诱导的人髓系白血病细胞凋亡。第二个目的是确定ATO诱导的细胞凋亡与VP-16相比是否受到蛋白激酶C（PKC）激活剂佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）的不同影响，据报道，佛波醇12-肉豆蔻酸酯13-乙酸酯可抑制某些化疗药物诱导的细胞凋亡。在存在和不存在半胱天冬酶蛋白酶抑制剂Z-VAD. favor或Y-VAD. cho的情况下，将NB 4和HL 60细胞与ATO一起孵育。以形态学、DNA梯状电泳和流式细胞术检测细胞凋亡，以聚腺苷二磷酸核糖聚合酶（PARP）裂解作为半胱氨酸蛋白酶（caspase）激活的标志。在ATO诱导的NB4和HL 60细胞凋亡过程中均发生PARP裂解。广谱抑制剂Z-VAD. fatal可阻断ATO诱导的细胞凋亡和PARP裂解，而caspase 1选择性抑制剂Y-VAD. cho则无此作用。PMA在已知激活PKC的条件下预孵育长达8小时对ATO或VP-16诱导的细胞凋亡均无影响。我们的结论是，在培养的髓系白血病细胞ATO诱导的细胞凋亡是由半胱天冬酶从远端，PARP裂解的激活级联的一部分，PKC激活没有影响ATO或VP-16诱导的细胞凋亡在这些细胞。
The primary objective of this study was to determine whether caspases are involved in arsenic trioxide(ATO)-induced apoptosis of human myeloid leukemia cells. A secondary objective was to determine whether apoptosis induced by ATO compared with VP-16 is differentially affected by an activator of protein kinase C (PKC), phorbol 12-myristate 13-acetate (PMA), which has been reported to inhibit apoptosis induced by some chemotherapeutic agents. NB4 and HL60 cells were incubated with ATO in the presence and absence of the caspase protease inhibitors Z-VAD.fmk or Y-VAD.cho. Apoptosis was assessed by morphology, DNA laddering and flow cytometry, Poly (ADP-ribose) polymerase (PARP) cleavage was used as a marker for the activation of caspases. PARP cleavage occurred during ATO-induced apoptosis in both NB4 and HL60 cells. Z-VAD.fmk, a broad-spectrum inhibitor, could block ATO-induced apoptosis and PARP cleavage, whilst Y-VAD.cho, a selective inhibitor of caspase 1, had no such effect, PMA pre-incubation for up to 8 hours under conditions known to activate PKC had no effect on either ATO- or VP-16-induced apoptosis. We conclude that in cultured myeloid leukemia cells ATO-induced apoptosis is executed by caspases from the distal, PARP-cleaving part of the activation cascade and that PKC activation has no effect on apoptosis induced by either ATO or VP-16 in these cells.