Abstract
Simple SummaryThe anticancer drug doxorubicin is widely used for the treatment of malignant tumors, including colon, breast, and ovary cancers. However, prolonged use of doxorubicin causes heart damage, ranging from changes in the structure and function of heart cells to heart failure, the condition in which the heart does not pump enough blood. As this problem affects the quality of life and survival of cancer patients, solutions to it are urgently needed. This study demonstrates that Chrysanthemum morifolium extract, an extract of the purple chrysanthemum flower, reduced the heart damage caused by doxorubicin by suppressing cell death in heart cells and heart failure in an animal model. As Chrysanthemum morifolium has been eaten since ancient times, the extract from this functional food is likely to be safe in clinical application, potentially allowing patients to receive the well-established anti-cancer benefits of doxorubicin without the side effect of heart damage.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.
Highlights
In recent years, the prognosis of patients with malignant neoplasm has been improving due to advances in surgical treatment, radiation therapy, and chemotherapy with anticancer drugs [1,2]
The results indicated that Fractional shortening (FS) and EF were decreased by DOX, and that Chrysanthemum morifolium extract (CME) suppressed these changes (Figure 5B,C)
CME suppressed in vitro the activation of caspase-3 and -9, which regulate DOXinduced apoptosis, as well as that of the tumor suppressor gene p53, which is upstream of these caspases in H9C2 cells
Summary
The prognosis of patients with malignant neoplasm has been improving due to advances in surgical treatment, radiation therapy, and chemotherapy with anticancer drugs [1,2]. The long-term survival of patients has increased the amount of cardiotoxicity caused by anticancer drugs, which had not been previously observed [3,4]. Cardiotoxicity caused by anticancer drugs is classified into two types according to clinical characteristics [6]. Type I anti-tumor agents, represented by anthracyclines, induce dose-dependent myocardial disorders with irreversible histochemical changes. Type II anti-tumor agents are dose-independent drugs that induce myocardial dysfunction with reversible histochemical changes. Doxorubicin (DOX) is indicated for various cancers, including malignant lymphoma, lung cancer, gastrointestinal cancer, breast cancer, and osteosarcoma. It is highly effective and is considered an essential treatment for these cancers.
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