期刊
TOXICOLOGY IN VITRO
卷 24, 期 6, 页码 1584-1591出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2010.06.009
关键词
Metallothionein; Doxorubicin; Cardiomyocytes; Reactive oxygen species
类别
资金
- National Natural Science Foundation of China [30873130]
- Ministry of Science and Technology of China [2009ZX09501-034]
The clinical use of doxorubicin (Dox), a potent anticancer drug, is limited by its concurrent dose-dependent cardiotoxicity. We previously found that metallothionein-I/II (MT-I/II) null mice are more vulnerable to Dox-induced cardiomyopathy, but it is unknown whether depletion of MT would sensitize cardiomyocytes to Dox toxicity in vitro since the protective effect of MT still remains controversial. In the present study, a primary culture system of cardiomyocytes from neonatal MT-I/II null (MT-/-) and corresponding wild type (MT+/+) mice was established to unequivocally determine the effect of MT deficiency on Dox-induced toxicity. MT concentrations in the MT-/- cardiomyocytes were about 2.5-fold lower than those in MT+/+ cardiomyocytes. MT-/- cardiomyocytes were more sensitive to Dox-induced cytotoxicity than MT+/+ cardiomyocytes as measured by morphological alterations, lactate dehydrogenase leakage, cell viability, and apoptosis. Dox time- and concentration-dependently increased reactive oxygen species (ROS) formation in MT+/+ cardiomyocytes, and this effect was exaggerated in MT-/- cardiomyocytes. Antioxidant N-acetylcysteine (NAC) and glutathione (GSH) significantly rescued MT+/+ but not MT(-/-)cardiomyocytes from Dox-induced cell death and ROS generation. These findings suggest that basal MT provide protection against Dox-induced toxicity in cardiomyocytes, particularly highlight the important role of MT as a cellular antioxidant on scavenging ROS. (C) 2010 Elsevier Ltd. All rights reserved.
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