lignans and Cardiomyopathies

Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity. We have recently identified honokiol (HKL) as an activator of SIRT3, which protects the heart from developing pressure overload hypertrophy. Here, we show that HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin. Doxorubicin-induced cardiotoxicity is associated with increased ROS production and consequent fragmentation of mitochondria and cell death. HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes. HKL also promoted mitochondrial fusion. We also show that treatment with HKL blocked doxorubicin-induced cardiac toxicity in mice. This was associated with reduced mitochondrial DNA damage and improved mitochondrial function. Furthermore, treatments of mice, bearing prostrate tumor-xenografts, with HKL and doxorubicin showed inhibition of tumor growth with significantly reduced cardiac toxicity. Our results suggest that HKL-mediated activation of SIRT3 protects the heart from doxorubicin-induced cardiotoxicity and represents a potentially novel adjunct for chemotherapy treatments.

Topics: Animals; Biphenyl Compounds; Cardiomyopathies; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Doxorubicin; Lignans; Mice; Mitochondria, Heart; Myocytes, Cardiac; Rats; Reactive Oxygen Species; Sirtuin 3; Up-Regulation

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.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiomyopathies; Cyclooctanes; Disease Models, Animal; Doxorubicin; Gene Expression Regulation; Lignans; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Polycyclic Compounds; Tyrosine; Ventricular Function, Left

In this study, it is to compare the effectiveness of prevention against and treatment of doxorubicin (DOX) induced cardiotoxicity by dexrazoxane and schisandrin B (Sch B) in rats. Sprague-Dawley (SD) rats were randomly divided into the following 6 groups: normal saline group, DOX group, DOX+DEX group, DOX+Sch B (80 mg x kg(-1)) group, DOX+Sch B (40 mg x kg(-1)) group and DOX+Sch B (20 mg x kg(-1)) group. The results showed that Sch B could combat the increase of myocardial enzymes in peripheral blood, decrease of the enzyme activity of myocardial tissue antioxidant enzymes and disorders of systolic and diastolic function of heart in rats intravenously injected with doxorubicin (15 mg x kg(-1)). Sch B was better than DEX in protecting rat against DOX-induced the symptoms. Sch B could protect rat against DOX-induced acute cardiomyopathy and has clinical potential applications.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Cardiomyopathies; Cardiotoxicity; Cyclooctanes; Dexrazoxane; Doxorubicin; Heart; Lignans; Myocardium; Polycyclic Compounds; Rats; Rats, Sprague-Dawley

To study the effect of dexrazoxane in preventing doxorubicin-induced cardiotoxicity in rabbit-models and its mechanism.. Thirty one New Zealand white rabbits were randomly divided into two groups, doxorubicin (DOX) group and doxorubicin + dexrazoxane group. The cardiotoxicity was assessed by measuring serum superoxide dismutase (SOD), malondialdehyde (MDA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP), left ventricular ejection function (LVEF), and left ventricular fractional shortening (LVFS), before and 4 and 10 weeks after intervention. Pathological changes in cardiac tissues and the apoptosis of myocardial cells were examined at the end of the experiment. Results Doxorubicin increased serum MDA, cTnI and BNP and decreased SOD, LVEF and LVFS (P < 0.05). Dexrazoxane (DEX) inhibited the increase of MDA, cTnI and BNP, and the decrease of LVEF and LVFS (P < 0.05). The rabbits treated with doxorubicin + dexrazoxane had slighter pathological changes in myocardium and apoptotic myocardial cells than those treated with DOX.. Dexrazoxane prevents doxorubicin-induced cardiotoxicity through decreasing oxygen free radical production, cutting down lipid peroxidation, and depressing cardiocyte apoptosis.

Topics: Animals; Apoptosis; Cardiomyopathies; Cyclooctanes; Doxorubicin; Female; Lignans; Lipid Peroxidation; Male; Natriuretic Peptide, Brain; Polycyclic Compounds; Rabbits; Random Allocation; Reactive Oxygen Species; Schisandraceae; Superoxide Dismutase; Troponin I