Mechanisms of N-acetylcysteine-driven enhancement of MK886-induced apoptosis
Mechanisms of N-acetylcysteine-driven enhancement of MK886-induced apoptosis
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DOI：
10.1007/s10565-006-0072-6
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发表时间：
2006-07-01
影响因子：
6.1
通讯作者：
Kehrer, James P.
中科院分区：
文献类型：
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作者：
Deshpande, V. S.;Kehrer, James P.
N-乙酰半胱氨酸(NAC)除了是谷胱甘肽的前体外，还具有一系列其他作用，包括清除自由基，调节基因表达和信号转导途径，以及调节细胞存活和凋亡。当NAC浓度低于20 mmoL/L时，对培养细胞无毒，并能对抗多种药物诱导的细胞凋亡。然而，最近的一些报道表明，NAC也可以增加细胞凋亡。MK886是一种5-脂氧合酶激活蛋白(FLAP)抑制剂，它通过一种未知的机制诱导许多细胞系的凋亡，该机制不依赖于FLAP和脂氧合酶的活性，但可能与对Akt等激酶的影响有关。在Jurkat T淋巴细胞中，NAC(10 mmol/L)可使MK886诱导的细胞凋亡率增加2.4倍。与单独使用NAC-MK886相比，经NAC-MK886处理后，caspase-3活性显著升高，线粒体跨膜电位降低。然而，MK886单独和MK886-NAC处理的细胞色素c的释放程度是相似的。10 mmoL/L NAc对MK886诱导的细胞凋亡的促进作用可能部分与此浓度的NAc引起的pH降低有关，因为酸性环境有利于激活效应半胱氨酸酶并触发线粒体的凋亡。然而，由于中和的NAC也促进了细胞凋亡(1.6倍)，我们认为NAC在增强MK886启动的凋亡途径中起到了直接作用。
N-Acetylcysteine (NAC), besides being a precursor of glutathione, has an array of other effects including an ability to scavenge free radicals, modulate gene expression and signal transduction pathways, and regulate cell survival and apoptosis. At concentrations lower than 20 mmol/L, NAC is nontoxic to cultured cells and can protect against apoptosis induced by a number of agents. A few recent reports, however, have indicated that NAC can also increase apoptosis. MK886, a 5-lipoxygenase activating protein (FLAP) inhibitor, induces apoptosis in many cell lines by an unknown mechanism that is independent of FLAP and lipoxygenase activity but is possibly related to effects on kinases such as Akt. In Jurkat T lymphocytes, NAC pretreatment (10 mmol/L) enhanced MK886-induced apoptosis by 2.4-fold. Following NAC-MK886 treatment, there was a significant increase in caspase-3 activity, and a decrease in mitochondrial transmembrane potential compared to MK886 alone. However, the extent of cytochrome c release was comparable between MK886 alone and MK886-NAC treatments. The enhancement of MK886-induced apoptosis by 10 mmol/L NAC appears to be partly related to a decrease in pH caused by this concentration of NAC, because an acidic environment favors activation of effector caspases and triggering of mitochondrial apoptosis. However, because neutralized NAC also enhanced apoptosis (1.6-fold), a direct role for NAC in augmenting the apoptotic pathways initiated by MK886 is suggested.