期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 43, 期 7, 页码 1061-1075出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.06.021
关键词
cisplatin; extracellular signal-regulated kinases; CYP2E 1; necrosis; apoptosis; glutathione; l-buthion in e-[R,S]-sulfoximine; thioredoxin; free radicals
资金
- NIAAA NIH HHS [R01 AA003312, R01 AA006610-21, R56 AA003312, AA06610] Funding Source: Medline
In a previous study, E47 HepG2 cells that overexpress human CYP2E1 were shown to be more sensitive to cisplatin than C34 cells that do not express CYP2E1. In this study, we found that this sensitivity was due to an earlier activation of ERK in the E47 cells compared to the C34 cells. Glutathione depletion by L-buthionine sulfoximine (BSO) enhanced cisplatin cytotoxicity via increasing production of reactive oxygen species (ROS) and activation of ERK. In contrast, elevation of glutathione by glutathione ethyl ester (GSHE) decreased cisplatin/BSO cytotoxicity by decreasing ROS production and ERK activation. Inhibition of ERK activation by U0126 protected against cisplatin/BSO cytotoxicity via inhibiting ROS production but not restoring intracellular glutathione content. Examination of the mode of cell death showed that U0126 inhibited cisplatin-induced necrosis but not apoptosis. Cisplatin-induced apoptosis was caspases-dependent; BSO switched cisplatin-induced apoptosis to necrosis via decreasing activity of caspases, and GSHE switched cisplatin/BSO-induced necrosis back to apoptosis through maintaining activity of caspases. Similar to GSHE, U0126 partially switched cisplatin/BSO induced necrosis to apoptosis via restoring activity of caspases. Cisplatin lowered levels of thioredoxin, especially in the presence of BSO. Although U0126 failed in restoring intracellular glutathione levels, it restored thioredoxin levels, which maintain the activity of the caspases. These results suggest that thioredoxin can replace glutathione to promote the active thiol redox state necessary for caspase activity, and thus glutathione and thioredoxin regulate the mode of cisplatin toxicity in E47 cells via redox regulation of caspase activity. (c) 2007 Elsevier Inc. All rights reserved.
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