Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin

• Published in: International journal of molecular sciences 2021-06, Vol.22 (12), p.6217
• Main Authors: Koczurkiewicz-Adamczyk, Paulina, Klaś, Katarzyna, Gunia-Krzyżak, Agnieszka, Piska, Kamil, Andrysiak, Kalina, Stępniewski, Jacek, Lasota, Sławomir, Wójcik-Pszczoła, Katarzyna, Dulak, Józef, Madeja, Zbigniew, Pękala, Elżbieta
• Format: Article
• Language: English
• Subjects: Apoptosis; Cancer; Cardiomyocytes; Cardiomyopathy; cardioprotection; Cardiotoxicity; Caspase-3; Cinnamic acid; cinnamic acid derivatives; combined therapy; Congestive heart failure; Cytoskeleton; Doxorubicin; Drug development; Enzymes; Heart failure; Hepatotoxicity; HERG protein; hiPSC-CM; Morphology; Motility; Oxidative stress; Pluripotency; Potassium channels (voltage-gated); Stem cells; Wound healing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22126217

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.