Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;182(18):4262-4280.
doi: 10.1111/bph.70085. Epub 2025 May 28.

Dexrazoxane protects against doxorubicin-induced cardiotoxicity in susceptible human living myocardial slices: A proof-of-concept study

Jort S A van der Geest  1   2 , Ilse R Kelters  1 , Bauke Arends  1 , Willem B van Ham  3 , Ernest Diez Benavente  1 , Thirza A Lapré  1   2 , Petra van der Kraak  4 , Pim van der Harst  1 , Arco J Teske  1 , Andreas Dendorfer  5 , M Mostafa Mokhles  6 , Pieter A Doevendans  1   7   8 , Teun P de Boer  3 , Linda W van Laake  1   2 , Joost P G Sluijter  1   2 , Vasco Sampaio-Pinto  1   2
Affiliations

Dexrazoxane protects against doxorubicin-induced cardiotoxicity in susceptible human living myocardial slices: A proof-of-concept study

Jort S A van der Geest et al. Br J Pharmacol. 2025 Sep.

Abstract

Background and purpose: The increasing number of cancer survivors has caused growing concern over chemotherapy-induced cardiotoxicity. This study aimed to investigate a novel human model of cardiotoxicity and explore cardioprotection.

Experimental approach: Living myocardial slices (LMS) were obtained from explanted end-stage heart failure hearts, then exposed to doxorubicin (Dox) to investigate cardiotoxic effects and to dexrazoxane (Dex) to explore cardioprotection. We assessed contractile function and glucose consumption, followed by evaluation of calcium transients, structural integrity and transcriptomic changes. Additionally, electrocardiogram (ECG) alterations were analysed in patients treated with anthracyclines to corroborate the cardiotoxicity findings from LMS.

Key results: We observed distinct functional responses to Dox, with LMS derived from some patients exhibiting high susceptibility to Dox-induced cardiotoxicity. LMS from susceptible patients displayed reduced contractile function and excitability, myofibre dyssynchrony, structural damage and decreased metabolic activity. Dex pretreatment partially mitigated these effects, preserving contractile function and preventing structural damage. Consistent with ex vivo findings, patients treated with anthracyclines exhibited acute and chronic alterations in T-, P- and R-wave morphology of the ECG, confirming variable susceptibility at the clinical level.

Conclusions and implications: We highlight the value of human LMS in studying Dox-induced cardiotoxicity and the cardioprotective potential of Dex, even when sourced from end-stage heart failure patients. Susceptible patients harboured cardiomyopathy-associated genetic mutations, suggesting that genetic screening including cardiomyopathy-associated genes, prior to anthracycline treatment, could enable improved patient risk stratification. We demonstrate the potential utility of ECG changes for early detection of subclinical cardiotoxicity.

Keywords: anthracyclines; cardiotoxicity; dexrazoxane; electrocardiogram; living myocardial slices.

PubMed Disclaimer

References

REFERENCES

    1. Akolkar, G., da Silva Dias, D., Ayyappan, P., Bagchi, A. K., Jassal, D. S., Salemi, V. M. C., Irigoyen, M. C., De Angelis, K., & Singal, P. K. (2017). Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin‐induced cardiomyopathy. American Journal of Physiology. Heart and Circulatory Physiology, 313(4), H795–h809. https://doi.org/10.1152/ajpheart.00253.2017
    1. Alam Khan, S., & Jawaid Akhtar, M. (2022). Structural modification and strategies for the enhanced doxorubicin drug delivery. Bioorganic Chemistry, 120, 105599. https://doi.org/10.1016/j.bioorg.2022.105599
    1. Alexander, S. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Buneman, O. P., Cidlowski, J. A., Christopoulos, A., Davenport, A. P., Fabbro, D., Spedding, M., Striessnig, J., Davies, J. A., Ahlers‐Dannen, K. E., … Zolghadri, Y. (2021). The Concise Guide to PHARMACOLOGY 2021/22: Introduction and other protein targets. British Journal of Pharmacology, 178(Suppl 1), S1–S26. https://doi.org/10.1111/bph.15537
    1. Aminkeng, F., Bhavsar, A. P., Visscher, H., Rassekh, S. R., Li, Y., Lee, J. W., Brunham, L. R., Caron, H. N., van Dalen, E. C., Kremer, L. C., van der Pal, H. J., Amstutz, U., Rieder, M. J., Bernstein, D., Carleton, B. C., Hayden, M. R., Ross, C. J., & Canadian Pharmacogenomics Network for Drug Safety Consortium. (2015). A coding variant in RARG confers susceptibility to anthracycline‐induced cardiotoxicity in childhood cancer. Nature Genetics, 47(9), 1079–1084. https://doi.org/10.1038/ng.3374
    1. Austin, D., Maier, R. H., Akhter, N., Sayari, M., Ogundimu, E., Maddox, J. M., Vahabi, S., Humphreys, A. C., Graham, J., Oxenham, H., Haney, S., Cresti, N., Verrill, M., Osborne, W., Wright, K. L., Goranova, R., Bailey, J. R., Kalakonda, N., Macheta, M., … Plummer, C. (2024). Preventing cardiac damage in patients treated for breast cancer and lymphoma. JACC: CardioOncology, 6(5), 684–696. https://doi.org/10.1016/j.jaccao.2024.07.010

LinkOut - more resources