Mechanism of cell death induction by nitroxide and hyperthermia.
Mechanism of cell death induction by nitroxide and hyperthermia.
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DOI：
10.1016/j.freeradbiomed.2005.10.064
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发表时间：
2006-04
影响因子：
7.4
通讯作者：
Qing‐Li Zhao;Y. Fujiwara;T. Kondo
中科院分区：
文献类型：
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作者：
Qing‐Li Zhao;Y. Fujiwara;T. Kondo
热应激和氮氧化物诱导活性氧（ROS）和促凋亡作用。基本的机制在很大程度上仍然难以捉摸。在这里，我们报告了克里思（2，2，6，6-四甲基哌啶-N-氧自由基）是一种有效的热敏剂，可促进人白血病U937细胞的细胞死亡。用克里思（Tempo）（10 mM，37°C/30 min）和高温（44°C/30 min）处理分别诱导30%和70-80%的细胞凋亡，这是通过EVDase介导的细胞色素c释放和DEVDase活化实现的。克里思/热组合也引起了细胞色素c的释放，但转换热诱导的细胞凋亡的特定固缩细胞死亡，导致不可挽回的抑制增殖。克里思和热应激，而不是组合，导致早期短暂的升高H2 O2/O2-和晚期诱导只有O2-，分别。线粒体Ca 2+超载是无法区分的任何治疗后。由于DEVDase活化，热应激诱导75%的细胞中的泛半胱天冬酶抑制剂zVAD-抑制性低Δ（线粒体膜电位）。相比之下，克里思通过剥夺线粒体H+梯度产生低-Δ ε。联合治疗通过不可逆的线粒体功能障碍诱导了97%的zVAD耐药低Δ λ细胞。因此，在ROS或线粒体Ca 2+的可能帮助下，克里思或热应激共同诱导线粒体介导的线粒体凋亡，并且当与高热组合时，克里思通过不可逆的线粒体功能障碍诱导不可修复的固缩细胞死亡而起致敏剂作用。
Heat stress and nitroxides induce reactive oxygen species (ROS) and proapoptotic effects. The underlying mechanisms remain largely elusive. Here we report that Tempo (2,2,6,6-tetramethylpiperidine-N-oxyl) is a potent thermosensitizer for promoting cell death in human leukemia U937 cells. Treatment with Tempo (10 mM, 37°C/30 min) and hyperthermia (44°C/30 min) induced 30 and 70–80% apoptosis, respectively, through Bax-mediated cytochrome c release and DEVDase activation. The Tempo/heat combination also caused Bax-mediated cytochrome c release, but switched heat-induced apoptosis to the particular pyknotic cell death, resulting in the irreparable inhibition of proliferation. Tempo and heat stress, but not the combination, caused an early transient elevation of H2O2/O2−and a late induction of only O2−, respectively. Mitochondrial Ca2+overloads were indistinguishable after any treatment. Heat stress induced the pan-caspase inhibitor zVAD-fmk-suppressible low-Δψ (mitochondrial membrane potential) in 75% of cells as a result of DEVDase activation. In contrast, Tempo yielded low-Δψ by deprivation of the mitochondrial H+gradient. The combined treatment induced 97% zVAD-resistant low-Δψ cells through irreversible mitochondrial dysfunction. Together, thus, Tempo or heat stress induced Bax-mediated mitochondrial apoptosis with the possible help of ROS or mitochondrial Ca2+, and Tempo when combined with hyperthermia acts a sensitizer by inducing irreparable pyknotic cell death through irreversible mitochondrial dysfunction.