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

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 car...

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Bibliographic Details
Published in:Molecular and cellular biochemistry 2005-02, Vol.270 (1-2), p.13-19
Main Authors: Youn, Ho-Joong, Kim, Ho-Shik, Jeon, Mi-Hee, Lee, Jung-Hee, Seo, Yun-Jee, Lee, Yong-Joon, Lee, Jeong-Hwa
Format: Article
Language:English
Subjects:
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
Cellular biology
Dose-Response Relationship, Drug
Doxorubicin - pharmacology
Enzyme Activation
Enzyme Inhibitors - pharmacology
Humans
Hydrogen Peroxide - metabolism
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - pathology
Poly(ADP-ribose) Polymerases - metabolism
Tetrazolium Salts - pharmacology
Thiazoles - pharmacology
Time Factors
Tumor Suppressor Protein p53 - metabolism
Up-Regulation
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Summary: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.
ISSN:0300-8177
1573-4919
DOI:10.1007/s11010-005-2541-2