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Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane
D B Sawyer1, R Fukazawa, M A Arstall
1Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
-The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis. In contrast, dexrazoxane (10 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to limit the toxicity of these drugs.
Insights
Anthracycline chemotherapy causes heart cell death. Lower doses induce programmed cell death (apoptosis), while higher doses cause necrosis. Dexrazoxane protects against apoptosis, suggesting a role for superoxide radicals in this toxicity.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Anthracycline antineoplastic agents are crucial in cancer treatment but cause significant cardiac toxicity.
- The mechanisms underlying anthracycline-induced cardiotoxicity, particularly myocyte apoptosis, are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of anthracycline-induced cardiotoxicity in rat ventricular myocytes.
- To differentiate between apoptosis and necrosis induced by varying daunorubicin concentrations.
- To evaluate the protective role of dexrazoxane against anthracycline-induced myocyte death.
Main Methods:
- Primary cultures of neonatal and adult rat ventricular myocytes were used.
- Cells were exposed to daunorubicin at different concentrations (≤1 µmol/L and ≥10 µmol/L).
- Apoptosis and necrosis were assessed, and reactive oxygen species generation was monitored using dichlorofluorescein (DCF).
Main Results:
- Daunorubicin (≤1 µmol/L) induced programmed cell death (apoptosis) in myocytes within 24 hours.
- Higher concentrations (≥10 µmol/L) induced necrotic cell death, without apoptotic markers.
- Dexrazoxane (10 µmol/L) prevented daunorubicin-induced apoptosis but not necrosis.
- A superoxide dismutase mimetic replicated dexrazoxane's antiapoptotic effect.
Conclusions:
- Anthracycline-induced myocyte apoptosis occurs at lower concentrations than necrosis.
- Superoxide anion generation may mediate anthracycline-induced apoptosis.
- Dexrazoxane's protective effect against apoptosis suggests a targeted therapeutic strategy for anthracycline cardiotoxicity.