Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment.

Abstract

The cardiotoxicity of adriamycin limits its clinical use as a powerful drug for solid tumors and malignant hematological disease. Although the precise mechanism by which it causes cardiac damage is not yet known, it has been suggested that apoptosis is the principal process in adriamycin-induced cardiomyopathy, which involves DNA fragmentation, cytochrome C release, and caspase activation. However, there has been no direct evidence for the critical involvement of caspase-3 in adriamycin-induced apoptosis. To determine the requirements for the activation of caspase-3 in adriamycin-treated cardiac cells, the effect of a caspase inhibitor on the survival of and apoptotic changes in H9c2 cells was examined. Exposure of H9c2 cells to adriamycin resulted in a time- and dose-dependent cell death, and the cleavage of pro-caspase-3 and of the nuclear protein poly (ADP'ribose) polymerase (PARP). However, neither the reduction of cell viability nor the characteristic morphological changes induced by adriamycin were prevented by pretreatment with the general caspase inhibitor z-VAD.FMK. In contrast, caspase inhibition effectively blocked the apoptosis induced by H202 in H9c2 cells, as determined by an MTT assay or microscopy. We also observed that p53 expression was increased by adriamycin, and this increase was not affected by the inhibition of caspase activity, suggesting a role for p53 in adriamycin-induced caspase-independent apoptosis in cardiac toxicity.

• Authors: Ho-Joong Youn, Ho-Shik Kim, Mi-Hee Jeon, Jung-Hee Lee, Yun-Jee Seo, Yong-Joon Lee, Jeong-Hwa Lee
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 270 Issue 1-2 Pg. 13-9 (Feb 2005) ISSN: 0300-8177 [Print] Netherlands
• PMID: 15792349 (Publication Type: Journal Article)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antibiotics, Antineoplastic
• Enzyme Inhibitors
• Tetrazolium Salts
• Thiazoles
• Tumor Suppressor Protein p53
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Doxorubicin
• Hydrogen Peroxide
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• Caspase 3
• Caspases
• thiazolyl blue

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis
• Blotting, Western
• Caspase 3
• Caspases (metabolism)
• Cell Death
• Cell Line
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Survival
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Humans
• Hydrogen Peroxide (metabolism)
• Myocytes, Cardiac (drug effects, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation