Induction of apoptosis in human myeloid leukemic cells by 1′-acetoxychavicol acetate through a mitochondrial- and Fas-mediated dual mechanism
Induction of apoptosis in human myeloid leukemic cells by 1′-acetoxychavicol acetate through a mitochondrial- and Fas-mediated dual mechanism
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DOI：
10.1158/1078-0432.ccr-1142-03
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发表时间：
2004-03-15
影响因子：
11.5
通讯作者：
Kizaki, M
中科院分区：
文献类型：
--
作者：
Ito, K;Nakazato, T;Kizaki, M
目的：本研究的目的是确定V-乙酰氧基胡椒酚乙酸酯（ACA）的抗白血病作用，从根茎的常用的民族药用植物大高良姜（菊科）。实验设计：我们评估了ACA对各种骨髓性白血病细胞在体外和体内的影响。结果：低剂量ACA通过诱导白血病细胞凋亡，显著抑制白血病细胞的生长。由于NB 4早幼粒细胞白血病细胞对ACA最敏感，我们使用NB 4细胞进行进一步分析。活性氧的产生触发ACA诱导的细胞凋亡。ACA诱导的NB 4细胞凋亡与线粒体跨膜电位（Deltapsim）的丧失和caspase-9的激活有关，表明ACA诱导的死亡信号通过线粒体氧应激途径介导。此外，ACA通过诱导casapse-8活性激活Fas介导的凋亡。用巯基抗氧化剂N-a-鲸蜡基-L-半胱氨酸（NAC）预处理不抑制半胱天冬酶-8活化，并且拮抗性抗Fas抗体ZB 4不阻断活性氧的产生，表明两种途径独立地参与ACA诱导的细胞凋亡。此外，ACA在体内的生存优势，在非肥胖糖尿病/严重联合免疫缺陷小鼠白血病模型，没有任何毒性effects.Conclusions：我们得出结论，ACA诱导髓系白血病细胞凋亡，通过独立的双途径。此外，ACA具有作为治疗髓系白血病的新型治疗剂的潜力。
Purpose: The purpose of this investigation was to determine the antileukemic effects of V-acetoxychavicol acetate (ACA) obtained from rhizomes of the commonly used ethno-medicinal plant Languas galanga (Zingiberaceae).Experimental Design: We evaluated the effects of ACA on various myeloid leukemic cells in vitro and in vivo. We further examined the molecular mechanisms of ACA-induced apoptosis in myeloid leukemic cells.Results: Low-dose ACA dramatically inhibited cellular growth of leukemic cells by inducing apoptosis. Because NB4 promyelocytic leukemic cells were most sensitive to ACA, we used NB4 cells for further analyses. Production of reactive oxygen species triggered ACA-induced apoptosis. ACA-induced apoptosis in NB4 cells was in association with the loss of mitochondrial transmembrane potential (Deltapsim) and activation of caspase-9, suggesting that ACA-induced death signaling is mediated through a mitochondrial oxygen stress pathway. In addition, ACA activated Fas-mediated apoptosis by inducing of casapse-8 activity. Pretreatment with the thiol antioxidant N-aCetyl-L-eysteine (NAC) did not inhibit caspase-8 activation, and the antagonistic anti-Fas antibody ZB4 did not block generation of reactive oxygen species, indicating that both pathways were involved independently in ACA-induced apoptosis. Furthermore, ACA had a survival advantage in vivo in a nonobese diabetic/severe combined immunodeficient mice leukemia model without any toxic effects.Conclusions: We conclude that ACA induces apoptosis in myeloid leukemic cells via independent dual pathways. In addition, ACA has potential as a novel therapeutic agent for the treatment of myeloid leukemia.