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Updated: Oct 30, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin
Paulina Koczurkiewicz-Adamczyk1, Katarzyna Klaś1, Agnieszka Gunia-Krzyżak2
1Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland.
Abstract:
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.
Insights
Cinnamic acid derivatives offer a multitargeted protective effect against doxorubicin (DOX)-induced cardiotoxicity by reducing oxidative stress and improving cardiomyocyte viability. These compounds show promise for developing new therapies to support patients undergoing DOX treatment.
Area of Science:
- Cardiovascular Pharmacology
- Drug-Induced Toxicity
- Medicinal Chemistry
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent, but its use is limited by severe cardiotoxicity, leading to heart failure.
- Current strategies to mitigate DOX-induced cardiotoxicity lack universal efficacy.
- Developing cardioprotective agents is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the potential of cinnamic acid (CA) derivatives as a novel therapeutic strategy against DOX-induced cardiotoxicity.
- To evaluate the protective mechanisms of CA derivatives on cardiomyocytes exposed to DOX.
- To assess the safety profile of promising CA derivatives.
Main Methods:
- Utilized rat (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as models for DOX cardiotoxicity.
- Assessed cardiomyocyte viability, oxidative stress markers, and apoptosis (caspase-3 and -7 levels).
- Performed wound-healing assays to evaluate cell motility and examined cytoskeleton integrity. Conducted safety analyses including hepatotoxicity, mutagenicity, and hERG channel interaction.
Main Results:
- CA derivatives significantly protected cardiomyocytes against DOX-induced toxicity, reducing oxidative stress and improving cell viability.
- Compounds downregulated caspase-3 and -7 levels, indicating an anti-apoptotic effect.
- CA derivatives prevented DOX-induced inhibition of cell motility and cytoskeleton damage. Preliminary safety assessments showed favorable profiles for lead compounds.
Conclusions:
- Cinnamic acid derivatives demonstrate a multidirectional protective effect against DOX-induced cardiotoxicity.
- These findings suggest CA derivatives as potential therapeutic leads for mitigating chemotherapy-related heart damage.
- Further research into the molecular mechanisms is warranted to advance these compounds towards clinical application.
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