期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/ijms22126217
关键词
doxorubicin; cardiotoxicity; combined therapy; cinnamic acid derivatives; cardioprotection; hiPSC-CM
资金
- National Science Centre, Poland [2016/21/D/NZ7/01546]
Cinnamic acid (CA) derivatives show a multitarget protective effect against DOX-induced cardiotoxicity by ameliorating oxidative stress and viability reduction in cardiomyocytes. Further research is encouraged to elucidate the exact molecular mechanism of these compounds' activity.
Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic's toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses-including hepatotoxicity, mutagenic potential, and interaction with the hERG channel-were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds' activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.
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