Quercetin decreases intracellular GSH content and potentiates the apoptotic action of the antileukemic drug arsenic trioxide in human leukemia cell lines
Quercetin decreases intracellular GSH content and potentiates the apoptotic action of the antileukemic drug arsenic trioxide in human leukemia cell lines
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DOI：
10.1016/j.bcp.2008.02.007
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发表时间：
2008-05-15
影响因子：
5.8
通讯作者：
Aller, Patricio
中科院分区：
文献类型：
--
作者：
Ramos, Adrian M.;Aller, Patricio
三氧化二砷（ATO）是一种治疗急性早幼粒细胞白血病的有效药物，但这种药物的成功应用可能偶尔需要使用致敏策略。本研究表明，黄酮类化合物槲皮素和黄菊花素与ATO协同诱导U937前祖细胞和其他人白血病细胞系（THP-1, HL-60）凋亡。ATO +槲皮素共处理引起线粒体跨膜电位耗解，刺激线粒体凋亡通路，细胞色素c和Omi/Htra2释放，XIAP和Bcl-X-L下调，Bax活化，引起caspase-8/Bid活化。Bcl-2过表达抑制了细胞色素c的释放和细胞凋亡，抑制了caspase-8的激活。槲皮素和金菊素单独使用或与ATO联合使用均可降低Akt磷酸化和细胞内谷胱甘肽含量。GSH消耗受l-丁硫氨酸-(S，R)-亚砜亚胺（BSO）敏感酶活性水平的调节，n -乙酰- l-半胱氨酸不能恢复GSH含量，也不能防止细胞凋亡。BSO治疗引起GSH耗竭和ato诱导的细胞凋亡，但不影响ara-C和顺铂诱导的细胞凋亡。作为例外，ATO加槲皮素在NB4急性早幼粒细胞白血病细胞中未能引起Akt去磷酸化和GSH耗竭，因此在诱导该细胞系凋亡中表现出较低的协同效应。结论是谷胱甘肽耗竭至少部分解释了槲皮素选择性增强ATO毒性，并且这种类黄酮可能用于提高抗白血病药物的临床疗效。(C) 2008爱思唯尔公司版权所有。
Arsenic trioxide (ATO) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, but successful application of this agent may occasionally require the use of sensitizing strategies. The present work demonstrates that the flavonoids quercetin and chrysin cooperate with ATO to induce apoptosis in U937 promonocytes and other human leukemia cell lines (THP-1, HL-60). Co-treatment with ATO plus quercetin caused mitochondrial transmembrane potential dissipation, stimulated the mitochondrial apoptotic pathway, as indicated by cytochrome c and Omi/Htra2 release, XIAP and Bcl-X-L down-regulation, and Bax activation, and caused caspase-8/Bid activation. Bcl-2 over-expression abrogated cytochrome c release and apoptosis, and also blocked caspase-8 activation. Quercetin and chrysin, alone or with ATO, decreased Akt phosphorylation as well as intracellular GSH content. GSH depletion was regulated at the level Of L-buthionine-(S,R)-sulfoximine (BSO)-sensitive enzyme activity, and N-acetyl-L-cysteine failed both to restore GSH content and to prevent apoptosis. Treatment with BSO caused GSH depletion and potentiated ATO-provoked apoptosis, but did not affect apoptosis induction by ara-C and cisplatin. As an exception, ATO plus quercetin failed to elicit Akt de-phosphorylation and GSH depletion in NB4 acute promyelocytic leukemia cells, and correspondingly exhibited low cooperative effect in inducing apoptosis in this cell line. It is concluded that GSH depletion explains at least in part the selective potentiation of ATO toxicity by quercetin, and that this flavonoid might be used to increase the clinical efficacy of the antileukemic drug. (C) 2008 Elsevier Inc. All rights reserved.