Ionizing radiation potentiates dihydroartemisinin-induced apoptosis of A549 cells via a caspase-8-dependent pathway.
Ionizing radiation potentiates dihydroartemisinin-induced apoptosis of A549 cells via a caspase-8-dependent pathway.
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电离辐射通过 Caspase-8 依赖性途径增强双氢青蒿素诱导的 A549 细胞凋亡
DOI：
10.1371/journal.pone.0059827
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Chen T;Chen M;Chen J
本研究旨在探讨双氢青蒿素（DHA）和电离辐射（IR）诱导人肺腺癌A549细胞凋亡的分子机制。DHA处理诱导浓度和时间依赖性活性氧（ROS）介导的细胞死亡，具有典型的凋亡特征，如线粒体膜电位（Δ Km）的破坏、半胱天冬酶激活、DNA片段化和磷脂酰丝氨酸（PS）外化。抑制caspase-8或-9可显着阻止DHA诱导的细胞活力下降和caspase-3的激活，表明caspase-8和-9在DHA诱导的细胞凋亡中发挥主导作用。促凋亡蛋白Bax而非巴克的沉默显著抑制DHA诱导的凋亡，其中Bax而非巴克被激活。与DHA处理相反，低剂量（2或4戈伊）IR诱导了长时间的ROS产生。有趣的是，IR处理24 h诱导G2/M期细胞阻滞，在处理后36 h消失。更重要的是，IR协同增强DHA诱导的ROS产生、caspase-8和-3的活化、不可修复的G2/M期阻滞和细胞凋亡，但不增强DHA诱导的Δ λ m损失和caspase-9的活化。综上所述，我们的研究结果有力地证明了DHA和低剂量IR联合治疗对A549细胞的显著协同作用，其中IR通过增强caspase-8介导的外源性途径在很大程度上增强DHA诱导的细胞凋亡。
This report is designed to explore the molecular mechanism by which dihydroartemisinin (DHA) and ionizing radiation (IR) induce apoptosis in human lung adenocarcinoma A549 cells. DHA treatment induced a concentration- and time-dependent reactive oxygen species (ROS)-mediated cell death with typical apoptotic characteristics such as breakdown of mitochondrial membrane potential (Δψm), caspases activation, DNA fragmentation and phosphatidylserine (PS) externalization. Inhibition of caspase-8 or -9 significantly blocked DHA-induced decrease of cell viability and activation of caspase-3, suggesting the dominant roles of caspase-8 and -9 in DHA-induced apoptosis. Silencing of proapoptotic protein Bax but not Bak significantly inhibited DHA-induced apoptosis in which Bax but not Bak was activated. In contrast to DHA treatment, low-dose (2 or 4 Gy) IR induced a long-playing generation of ROS. Interestingly, IR treatment for 24 h induced G2/M cell cycle arrest that disappeared at 36 h after treatment. More importantly, IR synergistically potentiated DHA-induced generation of ROS, activation of caspase-8 and -3, irreparable G2/M arrest and apoptosis, but did not enhance DHA-induced loss of Δψm and activation of caspase-9. Taken together, our results strongly demonstrate the remarkable synergistic efficacy of combination treatment with DHA and low-dose IR for A549 cells in which IR potentiates DHA-induced apoptosis largely by enhancing the caspase-8-mediated extrinsic pathway.
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