期刊
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
卷 31, 期 1, 页码 64-70出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/08923970802354762
关键词
Doxorubicin; CO; bilirubin; heme-oxygenase-1; apoptosis
资金
- Korea Research Foundation [KRF-2005-070-C00095, E00021, 2007-KRF-E00111, 2005-015-E00210]
- Ministry of Health and Welfare [A060520]
- Korea Science and Engineering Foundation(KOSEF) for Biofoods Research Program
- Ministry of Science and Technology
The clinical utility of anthracycline anticancer agents, especially doxorubicin (DOX), is limited by progressive toxic cardiomyopathy linked to cardiomyocyte apoptosis. This study examined the protective effects of CO and bilirubin on DOX-induced cardiomyocyte toxicity. In vitro, DOX significantly decreased the viability of H9c2 cells and increased apoptotic features, such as changes in nuclear morphology and caspase protease activation. CO and bilirubin significantly inhibited DOX-induced cell death and caspase-3 activation, which may be explained by increased Bcl-2 expression and inhibition of Bax expression. CO and bilirubin up-regulated the heme oxygenase-1 (HO-1), which was required for the protective effect of CO, and a single bilirubin treatment increased DOX-induced apoptosis in H9c2 cells. The inhibition of HO-1 with ZnPP resulted in a striking increase in apoptosis in the CO, bilirubin, and DOX-treated cells. Furthermore, HO-1 overexpression increased resistance against DOX-induced cytotoxicity in H9c2 cells. In conclusion, CO and bilirubin can inhibit DOX-induced apoptosis in H9c2 cardiomyocytes. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by protecting against cardiomyocyte death.
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