CO and bilirubin inhibit doxorubicin-induced cardiac cell death.

Abstract

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.

• Authors: Do-Sung Kim, Soo-Wan Chae, Hyung-Ryong Kim, Han-Jung Chae
• Journal: Immunopharmacology and immunotoxicology (Immunopharmacol Immunotoxicol) Vol. 31 Issue 1 Pg. 64-70 ( 2009) ISSN: 1532-2513 [Electronic] England
• PMID: 18756386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bax protein, rat
• Enzyme Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Protoporphyrins
• RNA, Small Interfering
• bcl-2-Associated X Protein
• zinc protoporphyrin
• Carbon Monoxide
• Doxorubicin
• Heme Oxygenase-1
• Caspase 3
• Bilirubin

Topics

• Animals
• Apoptosis (drug effects)
• Bilirubin (pharmacology)
• Carbon Monoxide (pharmacology)
• Caspase 3 (metabolism)
• Cell Line
• Cell Survival (drug effects)
• Doxorubicin (antagonists & inhibitors, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Heme Oxygenase-1 (antagonists & inhibitors, genetics, metabolism)
• Mice
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Protoporphyrins (pharmacology)
• RNA, Small Interfering (genetics)
• Rats
• Transfection
• bcl-2-Associated X Protein (metabolism)