Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: The role of reactive oxygen and nitrogen intermediates
Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: The role of reactive oxygen and nitrogen intermediates
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DOI：
10.1006/abbi.1999.1337
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发表时间：
1999-08-15
影响因子：
3.9
通讯作者：
Kalyanaraman, B
中科院分区：
文献类型：
--
作者：
Konorev, EA;Kennedy, MC;Kalyanaraman, B
强力抗肿瘤抗生素阿霉素(DOX)的使用受到阻碍，因为它具有严重的心脏毒性，导致心肌病和心力衰竭的发生。在本研究中，我们利用原代成年大鼠心肌细胞建立了DOX致心肌损伤的细胞培养模型，在无血清条件下培养的大鼠心肌细胞暴露于1~40 mU的DOX，DOX可引起培养的心肌细胞释放肌醇酶乳酸脱氢酶(LDH)，这种释放可被细胞通透性超氧化物歧化酶(SOD)模拟物(MnTBAP)阻止，但不受细胞非通透性SOD酶或硫酸锰(II)的影响。谷胱甘肽过氧化物酶(GPX)的类似物Ebselen可增强MnTBAP对心肌细胞的保护作用，DOX可增加心肌细胞内氧化剂的生成，而MnTBAP可降低DOX诱导的细胞内氧化剂的含量，此外，DOX选择性灭活心肌细胞内的乌头酸酶，而MnTBAP可部分逆转这种失活。Ebselen进一步增强了MnTBAP对乌头酸酶活性的保护作用。这些结果表明，SOD模拟物MnTBAP可预防DOX对心肌细胞的损伤，GPX模拟物ebselen协同增强了MnTBAP的心脏保护作用，并讨论了这些发现与将癌症治疗中的心脏毒性降至最低的相关性。(C)1999年学术出版社。
The use of the potent antitumor antibiotic doxorubicin (DOX) is hampered because of its severe cardiac toxicity that leads to the development of cardiomyopathy and heart failure. In this study, we have developed a cell culture model for DOX-induced myocardial injury using primary adult rat cardiomyocytes that were cultured in serum-free medium and exposed to 1 to 40 mu M DOX, DOX caused a dose-dependent release of sarcosolic enzyme lactate dehydrogenase (LDH) from cultured myocytes, The release of LDH was prevented by the cell-permeable superoxide dismutase (SOD) mimetic (MnTBAP), but was unaffected by either cell-impermeable SOD enzyme, or manganese (II) sulfate. Ebselen, a glutathione peroxidase (GPx) mimetic, enhanced the protection of cardiomyocytes afforded by MnTBAP, DOX caused the increased formation of oxidants in cardiomyocytes, and MnTBAP lowered the amount of intracellular oxidants induced by DOX, In addition, DOX selectively inactivated aconitase in cardiomyocytes, and MnTBAP partially reversed this inactivation. Ebselen further amplified the protective effect of MnTBAP on aconitase activity. These results suggest that the SOD mimetic MnTBAP prevents DOX-induced damage to cardiomyocytes and that the GPx mimetic ebselen synergistically enhanced the cardioprotection afforded by MnTBAP, Relevance of these findings to minimizing cardiotoxicity in cancer treatment is discussed. (C) 1999 Academic Press.