What is the clinical evidence from this study?

Study design: Other. Population: Doxorubicin-induced cardiotoxicity. Intervention: Doxorubicin vs. Untreated controls. Primary outcome: Apoptosis and caspase-3 activity.

What does this research mean for the field?

Doxorubicin induces apoptosis through the activation of caspase-3 in cultured cardiomyocytes and rat ventricles, indicating that apoptosis plays a critical role in the progression of doxorubicin-induced cardiomyopathy. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

January 1, 2006Open Access

Doxorubicin Induces Apoptosis by Activation of Caspase-3 in Cultured Cardiomyocytes In Vitro and Rat Cardiac Ventricles In Vivo

Key Result

Doxorubicin induces apoptosis through the activation of caspase-3 in cultured cardiomyocytes and rat ventricles, suggesting apoptosis plays an important role in DOX-induced cardiomyopathy.

Structured PICO

Population

Primary cultured cardiomyocytes from neonatal Sprague-Dawley rats (in vitro) and 8-week-old male Sprague-Dawley rats (in vivo, n=30)

Intervention

Doxorubicin (10^-6 M for 24 hours in vitro; 3 mg/kg intravenously weekly for 5 weeks in vivo)

Comparator

Untreated cardiomyocytes (in vitro) and saline intravenously weekly for 5 weeks (in vivo)

Outcome

Apoptosis evaluated by DNA laddering, caspase-3 and -8 activity, TUNEL staining, and cardiac function by echocardiographysurrogate

Doxorubicin induces apoptosis in cardiomyocytes via the activation of caspase-3, suggesting a mitochondrial pathway plays a crucial role in doxorubicin-induced cardiomyopathy.

Abstract

Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.

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