Evidence that oxidative stress-induced apoptosis by menadione involves Fas-dependent and Fas-independent pathways
Evidence that oxidative stress-induced apoptosis by menadione involves Fas-dependent and Fas-independent pathways
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DOI：
10.1006/clim.2001.5129
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发表时间：
2001-12-01
影响因子：
8.6
通讯作者：
Nel, A
中科院分区：
文献类型：
--
作者：
Laux, I;Nel, A
美那酮（维生素K-3）是一种氧化还原循环醌，是临床上重要的化疗药物。本研究的目的是阐明甲萘醌诱导淋巴母细胞样细胞系细胞死亡的细胞毒性机制。我们的研究结果表明，虽然Jun激酶级联和FasL表达可能在较低的药物浓度下导致细胞死亡，但在较高的甲萘醌浓度下，线粒体途径主导了细胞毒性作用。甲萘醌可诱导Jurkat T细胞内跨膜电位（Delta Psi (m)）的降低和内膜质量的减少，从而明显影响Jurkat T细胞的线粒体功能，而n -乙酰半胱氨酸可完全逆转这一变化。重要的是，虽然广泛的fmk衍生的caspase抑制剂对fas诱导的细胞凋亡有强有力的影响，但它们不能干扰menadione的细胞毒性，这表明menadione诱导的细胞死亡主要与fas无关。此外，线粒体的变化与ATP的消耗一致。ATP产生的失败解释了fas非依赖性死亡事件的发生。(C) 2001 Elsevier Science。
Menadione (vitamin K-3) a redox cycling quinone, is a clinically important chemotherapeutic agent. The objective of this study was to clarify the cytotoxic mechanisms by which menadione induces cell death in a lymphoblastoid cell line. Our results show that while the Jun kinase cascade and FasL expression may contribute to cell death at lower drug concentrations, a mitochondrial pathway dominates the cytotoxic effect at higher menadione concentrations. Menadione treatment clearly affected the mitochondrial function of Jurkat T cells by inducing a collapse of the inner transmembrane potential (Delta Psi (m)) and a decrease in inner membrane mass, which could be completely reversed by N-acetylcysteine. Importantly, while a broad range of fmk-derived caspase inhibitors had potent effects on Fas-induced apoptosis, they failed to interfere in menadione cytotoxicity, indicating that menadione-induced cell death is predominantly Fas-independent. In addition, the mitochondrial changes coincided with ATP depletion. The failure in ATP production explains the occurrence of Fas-independent death events. (C) 2001 Elsevier Science.