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3-Indolepropionic acid mitigates sub-acute toxicity in the cardiomyocytes of epirubicin-treated female rats

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Abstract

Epirubicin (EPI) is an effective chemotherapeutic against breast cancer, though EPI-related cardiotoxicity limits its usage. Endogenously derived 3-indolepropionic acid (3-IPA) from tryptophan metabolism is of interest due to its antioxidant capabilities which may have cardioprotective effects. Supplementation with 3-IPA may abate EPI's cardiotoxicity, and herein we studied the possibility of lessening EPI-induced cardiotoxicity in Wistar rats. Experimental rats (n = 30; BW 180–200 g) were randomly distributed in five cohorts (A–E; n = 6 each). Group A (control), Group B (EPI 2.5 mg/mL), and group C (3-IPA 40 mg/kg) while Groups D and E were co-treated with EPI (2.5 mg/mL) together with 3-IPA (D: 20 and E: 40 mg/kg). Following sacrifice, oxidative status, lipid profile, transaminases relevant to cardiac function, and inflammatory biomarkers were analysed. Also, 8-hydroxyl-2'-deoxyguanosine (8-OHdG) and cardiac troponin T (cTnT) levels were assessed using an enzyme-linked immunosorbent assay (ELISA). EPI-initiated increases in cardiotoxicity biomarkers were significantly (p < 0.05) reduced by 3-IPA supplementation. Decreased antioxidant and increases in reactive oxygen and nitrogen species (RONS), 8-OHdG and lipid peroxidation were lessened (p < 0.05) in rat hearts co-treated with 3-IPA. EPI-induced increases in nitric oxide and myeloperoxidase were reduced (p < 0.05) by 3-IPA co-treatment. In addition, 3-IPA reversed EPI-mediated alterations in alanine aminotransferase (ALT), aspartate amino transaminases (AST), lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and serum lipid profile including total cholesterol and triglycerides. Microscopic examination of the cardiac tissues showed that histopathological lesions severity induced by EPI was lesser in 3-IPA co-treated rats. Our findings demonstrate that supplementing endogenously derived 3-IPA can enhance antioxidant protection in the cardiac tissue susceptible to EPI toxicity in female rats. These findings may benefit breast cancer patients undergoing chemotherapy by further validating these experimental data.

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Data availability

The data used are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Cancer Research and Molecular Biology Research Laboratories, Department of Biochemistry, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State, 200004, Nigeria

    Solomon Owumi, Moses Otunla & Grace Adebisi

  2. School of Chemistry & Biochemistry, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332-0400, USA

    Uche Arunsi

  3. Department of Cancer Immunology and Biotechnology, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK

    Ahmad Altayyar

  4. Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA

    Chioma Irozuru

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  1. Solomon Owumi
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Contributions

S. O, U.A, M.O, M. A, C.I and G. A: Conceptualization. U.A, M.O, M.A, C.I and G. A, and Project administration, data curation, analysis, investigation. S. O: Supervision, Visualization, validation. S. O, U.A, M.O, M. A, C.I and G. A: Writing, review, and editing. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Solomon Owumi.

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The protocol for this rodent study conforms to the University of Ibadan Animal Care and Use Research Ethics Committee (ACUREC) UI-ACUREC/034–0521/7 and the United States National Institute of Health (NIH) guide for the care and use of laboratory animals. All procedures followed the ARRIVE (Animal Research Reporting In Vivo Experiments) guidelines. Furthermore, we adhered to the 3-R guidelines for (replacement, reduction, and refinement) for this study’s care and use of experimental animals.

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Owumi, S., Arunsi, U., Otunla, M. et al. 3-Indolepropionic acid mitigates sub-acute toxicity in the cardiomyocytes of epirubicin-treated female rats. Naunyn-Schmiedeberg's Arch Pharmacol 397, 507–520 (2024). https://doi.org/10.1007/s00210-023-02618-y

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