Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via Fas/caspase-8-dependent pathway in human lymphoma U937 cells
Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via Fas/caspase-8-dependent pathway in human lymphoma U937 cells
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DOI：
10.1016/j.cbi.2007.07.007
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发表时间：
2007-11-20
影响因子：
5.1
通讯作者：
Kondo, Takashi
中科院分区：
文献类型：
--
作者：
Ahmed, Kanwal;Zhao, Qing-Li;Kondo, Takashi
研究了大球体（MS）核心（天然MS的简化16元核心结构）衍生物诱导人淋巴瘤U937细胞凋亡的能力。在检测的五种化合物中，在8和14位具有酮的MS核心（MS 5）显示出诱导细胞凋亡的最高效力，而另一种具有一个酮的MS 3的效力最小。DNA片段化分析证实，MS 5以时间和剂量依赖性方式诱导U937细胞凋亡。MS 5处理的细胞表现出细胞内活性氧（ROS），谷胱甘肽耗竭，Bid激活和脂质过氧化反应的增加。用pancaspase抑制剂预处理细胞导致MS 5诱导的凋亡的完全抑制。N-乙酰-L-半胱氨酸（NAC）预处理导致谷胱甘肽浓度增加，细胞内ROS减少，DNA断裂完全抑制，线粒体膜电位（MMP）崩溃，Fas外化和caspase-8激活。此外，MS 5诱导的氧化应激还引发细胞内钙离子（[Ca 2 +]（i））浓度的瞬时增加，NAC完全抑制。用细胞内Ca 2+螯合剂预处理，BAPTA-AM减少了MS 5诱导的DNA片段化和caspase-8活化，而对MMP崩溃的影响很小。总之，我们目前的数据表明，MS 5通过Fas/半胱天冬酶-8介导的线粒体途径快速增加细胞内ROS引发细胞凋亡，这表明二酮的存在使化合物更有效地诱导细胞凋亡。MS 5的这些特性将使其可用于靶向细胞凋亡的治疗应用。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
The ability of the derivatives of macrosphelides (MS) core (simplified 16-membered core structure of natural MS) to induce apoptosis in human lymphoma U937 cells was investigated. Of the five compounds examined, MS core with ketones at 8 and 14 positions (MS5) showed the highest potency to induce apoptosis, while another, MS3 with one ketone, was minimal potent. MS5 was found to induce apoptosis in the U937 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis. MS5 treated cells showed increase in intracellular reactive oxygen species (ROS), glutathione depletion, Bid activation and lipid peroxidation. Pretreatment of cells with pancaspase inhibitor resulted in the complete inhibition of MS5-induced apoptosis. N-Acetyl-L-cysteine (NAC pretreatment resulted in the increase in glutathione concentration, reduction of intracellular ROS, complete inhibition of DNA fragmentation, mitochondrial membrane potential (MMP) collapse, Fas externalization and caspase-8 activation. Furthermore, MS5-induced oxidative stress also triggered transient increase in intracellular calcium ion ([Ca2+](i)) concentration which was completely inhibited by NAC. Pretreatment with an intracellular Ca2+ chelator, BAPTA-AM reduced MS5-induced DNA fragmentation and caspase-8 activation while it has marginal effects on MMP collapse. Taken together our present data showed that a rapid increase in intracellular ROS by MS5 triggers apoptosis via the Fas/caspase-8-mediated mitochondrial pathway suggesting that the presence of diketone makes the compound more potent to induce apoptosis. These characteristics of MS5 will make it useful for therapeutic applications of targeted apoptosis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.