Abstract
Doxorubicin (Dox) is a highly effective antineoplastic drug. However, Dox-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy, which limits Dox clinical application. Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In current study, we investigated possible protective effects of Sch B against Dox-induced cardiomyopathy in mice. Mice received a single injection of Dox (20 mg/kg IP). Five days after Dox administration, left ventricular (LV) performance was significantly depressed and was improved by Sch B treatment. Sch B prevented the Dox-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart. In addition, the increased expression of phospho-p38 MAPK and phospho-MAPK activated mitogen kinase 2 levels by Dox were significantly suppressed by Sch B treatment. Sch B also attenuated Dox-induced higher expression of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3 positive cells and phopho-p53 levels in mice. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species were significantly less in Sch B treatment mice after Dox injection. These findings suggest that Sch B attenuates Dox-induced cardiotoxicity via antioxidative and anti-inflammatory effects.
Highlights
Doxorubicin (Dox) is one of the most frequently used anticancer agents in the treatment of both solid and hematologic malignancies
We showed that Schisandrin B (Sch B) inhibited the Dox induced p53 phosphorylation, proinflammatory cytokines, ROS production and oxidative stress, nitrative stress, cardiomyocyte DNA damage, transferase-meditated dUTP nick-end labeling (TUNEL)-positive cells in the myocardium, and caspase-3 positive cells, which were associated with cardiac dysfunction
These results provide adequate evidence that Sch B possesses beneficial properties against Dox toxicity, and raises this herbal agent a potential therapeutic adjuvant that may prevent the heart from the serious side effect of Dox
Summary
Doxorubicin (Dox) is one of the most frequently used anticancer agents in the treatment of both solid and hematologic malignancies. The Dox-induced cardiotoxicity is characterized by left ventricular (LV) dysfunction, often leading to congestive heart failure with poor prognosis [1]. The mechanisms of Dox-induced cardiomyopathy are not fully understood, but a solid body of evidence indicates that oxidative stress and cardiac inflammation are involved [3]. We and others showed previously that both attenuated cardiac cytokine activation and lipid peroxidation might contribute to improved LV function in a mouse model of Dox-induced cardiotoxicity [3, 4]. Accumulating evidence indicates that Dox-induced cardiomyopathy is mainly caused by increased oxidant production, which eventually leads to the apoptotic loss of cardiomyocytes [6,7,8]. The search for an effective and safe antagonist of Dox cardiac toxicity remains a critical issue in both cardiology and oncology
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