It is well known that the anthracycline anticancer drug doxorubicin (DOX) induces cardiotoxicity. Recently, Chrysanthemum morifolium extract (CME), an extract of the purple chrysanthemum flower, has been reported to possess various physiological activities such as antioxidant and anti-inflammatory effects. However, its effect on DOX-induced cardiotoxicity is still unknown. An 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT)assay revealed that 1 mg/mL of CME reduced DOX-induced cytotoxicity in H9C2 cells but not in MDA-MB-231 cells. A TUNEL assay indicated that CME treatment improved DOX-induced apoptosis in H9C2 cells. Moreover, DOX-induced increases in the expression levels of p53, phosphorylated p53, and cleaved caspase-3,9 were significantly suppressed by CME treatment. Next, we investigated the effect of CME in vivo. The results showed that CME treatment substantially reversed the DOX-induced decrease in survival rate. Echocardiography indicated that CME treatment also reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that CME treatment also suppressed apoptosis in the mouse heart. These results reveal that CME treatment ameliorated DOX-induced cardiotoxicity by suppressing apoptosis. Further study is needed to clarify the effect of CME on DOX-induced heart failure in humans.

Background: Doxorubicin is widely used for the treatment of various malignant tumors. However, doxorubicin causes cumulative and dose-dependent cardiotoxicity, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive heart failure. Since this problem affects the QOL and survival of cancer patients, solutions for this problem are urgently needed. Recently, it has been reported that Chrysanthemum morifolium extracts (CME) have antioxidant and anti-inflammatory activities. The purpose of this study is to clarify whether CME decreases doxorubicin-induced cardiotoxicity and prevents the development of heart failure. Methods and Results: H9C2 cardiomyoblast cells were treated with CME (0.3, 1 mg/mL) for 2 hours and then stimulated with doxorubicin. After 24 hours incubation, surviving cells were evaluated by MTT assay. CME dose-dependently decreased doxorubicin-induced cardiotoxicity in H9C2 cells. Western blotting showed that CME significantly suppressed doxorubicin-induced increases in four markers of apoptosis: p53, phosphorylated p53, and cleaved caspase-9 and -3. Next, to investigate the effects of CME on doxorubicin-induced cardiomyopathy in vivo, C57BL6 mice were orally administered with CME (400 mg/kg/day) or vehicle daily from 2 days before doxorubicin treatment and then treated once intraperitoneally with doxorubicin (20 mg/kg). The survival ratio of the CME-treated group was significantly higher than that of the vehicle-treated group. Echocardiographic analysis at 7 days after doxorubicin stimulation revealed that CME had significantly improved doxorubicin-induced left ventricular systolic dysfunction. Apoptotic cells in mouse heart tissue were detected by TUNEL assay, which showed that CME significantly suppressed doxorubicin-induced apoptosis. Discussion: These results indicate that CME decreases doxorubicin-induced cardiotoxicity both in vitro and in vivo, suggesting that CME might possess the therapeutic potency to reduce doxorubicin-induced cardiotoxicity in cancer patients. Further studies are required to assess the effectiveness of CME for preventing doxorubicin-induced heart failure in clinical settings.