Doxorubicin-induced cardiotoxicity model elaboration in rats and rabbits

DOI: 10.29296/2618723X-2021-04-05

E.V. Mazukina, Department of Experimental Pharmacology and Toxicology, researcher. ORCID 0000-0002-1448-921X

E.V. Shekunova, PhD, Department of Experimental Pharmacology and Toxicology, head. ORCID 0000-0002-2689-6891

Ya.A. Guschin, Department of laboratory diagnostics, head. ORCID 0000-0002-7656-991Х

N.M. Faustova, PhD, Laboratory for enzyme immunoassay, head. ORCID 0000-0002-6866-5741

Research and manufacturing company «Home оf Pharmacy»,
188663, Russia, Leningrad oblast, Vsevolozhskiy district, Kuzmolovskiy t.s., Zavodskaya st. 3-245

E-mail: [email protected]

Keywords: Doxorubicin cardiotoxic effect rats rabbits

For citation:

Mazukina E.V., Shekunova E.V., Guschin Ya.A., Faustova N.M. Doxorubicin-induced cardiotoxicity model elaboration in rats and rabbits. Laboratory Animals for Science. 2021; 4.


Doxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. The establishing approaches to prevent DOX-mediated cardiotoxicity are urgent task. Experimental studies are needed for testing the effectiveness of innovative drugs. There are many methods describing. The literature describes various methodological approaches to the experimental modeling of DOX-induced cardiotoxicity.

The aim of the study: to reproduce the methods of DOX-induce cardiotoxicity in rats and rabbits based on scientific literature for further evaluation of the effectiveness of the cardioprotective properties of drugs.

Methods: rats were treated with DOX 2.5–5.0 mg/kg, intraperitoneally twice a week for 4 weeks;  cumulative doses were 20–32.5 mg/kg. Rabbits were treated with DOX 1.0 mg/kg, intravenously twice a week for 4 or 6 weeks, cumulative doses were 8 and 12 mg/kg. Assessment of cardiovascular function was made using electrocardiography (ECG) and blood pressure (BP) recording. The markers of oxidative stress (malondialdehyde, reduced glutathione) were also evaluated. The effect of doxorubicin on the myocardium was investigated with histological analysis.

Results: DOX administration, 5 mg/kg, resulted in high mortality rate (90%) in rats. Thus, this dose should not be used for DOX cardiotoxicity assessment. The least dose used (2.5 mg/kg) caused mild parameters changes. The mortality rate was around 20%. The DOX at doses 3.0–3.5 mg/kg resulted in severe myocardium histology changes, cardiac dysfunction (assesses by ECG), changes of antioxidant system parameters. The mortality rate at these doses was lower than that at dose 5 mg/kg (30–40%). Thus, DOX administration schedule at doses 3.0–3.5 for 4 weeks may be used to assess DOX cardiotoxicity.

In the rabbit study repeated intravenous DOX administration at dose 1 mg/kg caused severe myocardium histology changes indicating cardiotoxicity. The animals did not demonstrate any sigh of clinical abnormalities. In spite of presense of DOX-induced myocardial lesions, oxidative stress markers (malondialdehyde), blood pressure, ECG did not change significantly. There was high individual variability of these parameters. It could be speculated that to induce severe changes in oxidative stress markers the more prolong DOX administration is needed (up to 8 weeks).

Full text avaliable in Russain only 


The study was performed without external funding.

Authors’ contributions

E.V.Mazukina – conducting experiments, collecting data, analyzing data, writing a manuscript.

E.V. Shekunova – development of the research concept, data analysis, participation in the writing of the manuscript, critical revision of the content of the article.

Ya.A. Gushchin – pathomorphological analysis, participation in the writing of the manuscript

N.M. Faustova – conducting biochemical research, participating in the writing of the manuscript.

Conflict of interest

The authors declare no conflicts of interest.


  1. Инструкция по медицинскому применению лекарственного препарата Доксорубицин. ЛП-006268-170620. ‒. ‒ URL: (дата обращения: 06/2021).
  2. Lai R., Long Y., Li Q., Zhang X., Rong T. Oxidative stress markers may not be early markers of doxorubicin-induced cardiotoxicity in rabbits // Exp Ther Med. ‒ 2011. ‒ V. 2, № 5. ‒ P. 947-950. 10.3892/etm.2011.306.
  3. Zhou S., Palmeira C. M., Wallace K. B. Doxorubicin-induced persistent oxidative stress to cardiac myocytes // Toxicol Lett. ‒ 2001. ‒ V. 121, № 3. ‒ P. 151-7. 10.1016/s0378-4274(01)00329-0.
  4. Shaker R. A., Abboud S. H., Assad H. C., Hadi N. Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis // BMC Pharmacol Toxicol. ‒ 2018. ‒ V. 19, № 1. ‒ P. 3. 10.1186/s40360-017-0184-z.
  5. Podyacheva E. Y., Kushnareva E. A., Karpov A. A., Toropova Y. G. Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician // Front Pharmacol. ‒ 2021. ‒ V. 12. ‒ P. 670479. 10.3389/fphar.2021.670479.
  6. Russo M., Guida F., Paparo L., Trinchese G., Aitoro R., Avagliano C., Fiordelisi A., Napolitano F., Mercurio V., Sala V., Li M., Sorriento D., Ciccarelli M., Ghigo A., Hirsch E., Bianco R., Iaccarino G., Abete P., Bonaduce D., Calignano A., Berni Canani R., Tocchetti C. G. The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity // Eur J Heart Fail. ‒ 2019. ‒ V. 21, № 4. ‒ P. 519-528. 10.1002/ejhf.1439.
  7. Zeiss C. J., Gatti D. M., Toro-Salazar O., Davis C., Lutz C. M., Spinale F., Stearns T., Furtado M. B., Churchill G. A. Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans // G3 (Bethesda). ‒ 2019. ‒ V. 9, № 8. ‒ P. 2637-2646. 10.1534/g3.119.400232.
  8. Yin Z., Zhao Y., Li H., Yan M., Zhou L., Chen C., Wang D. W. miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway // Aging (Albany NY). ‒ 2016. ‒ V. 8, № 1. ‒ P. 192-207. 10.18632/aging.100876.
  9. Bai Z., Wang Z. Genistein protects against doxorubicin-induced cardiotoxicity through Nrf-2/HO-1 signaling in mice model // Environ Toxicol. ‒ 2019. ‒ V. 34, № 5. ‒ P. 645-651. 10.1002/tox.22730.
  10. Ma Z. G., Kong C. Y., Wu H. M., Song P., Zhang X., Yuan Y. P., Deng W., Tang Q. Z. Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice // Theranostics. ‒ 2020. ‒ V. 10, № 24. ‒ P. 11013-11025. 10.7150/thno.47516.
  11. Liu G., Liu Y., Wang R., Hou T., Chen C., Zheng S., Dong Z. Spironolactone Attenuates Doxorubicin-induced Cardiotoxicity in Rats // Cardiovasc Ther. ‒ 2016. ‒ V. 34, № 4. ‒ P. 216-24. 10.1111/1755-5922.12189.
  12. Adıyaman M., Adıyaman Ö A., Dağlı A. F., Karahan M. Z., Kaya İ., Dağlı M. N. Effects of grapeseed extract on doxorubicin-induced cardiotoxicity in rats // Herz. ‒ 2021. ‒ V. 46, № Suppl 1. ‒ P. 103-108. 10.1007/s00059-019-04888-w.
  13. Zilinyi R., Czompa A., Czegledi A., Gajtko A., Pituk D., Lekli I., Tosaki A. The Cardioprotective Effect of Metformin in Doxorubicin-Induced Cardiotoxicity: The Role of Autophagy // Molecules. ‒ 2018. ‒ V. 23, № 5. 10.3390/molecules23051184.
  14. Tian W., Yang L., Liu Y., He J., Yang L., Zhang Q., Liu F., Li J., Liu J., Sumi S., Shen Y., Qi Z. Resveratrol attenuates doxorubicin-induced cardiotoxicity in rats by up-regulation of vascular endothelial growth factor B // J Nutr Biochem. ‒ 2020. ‒ V. 79. ‒ P. 108132. 10.1016/j.jnutbio.2019.01.018.
  15. Al-Taee H., Azimullah S., Meeran M. F. N., Alaraj Almheiri M. K., Al Jasmi R. A., Tariq S., Ab Khan M., Adeghate E., Ojha S. β-caryophyllene, a dietary phytocannabinoid attenuates oxidative stress, inflammation, apoptosis and prevents structural alterations of the myocardium against doxorubicin-induced acute cardiotoxicity in rats: An in vitro and in vivo study // Eur J Pharmacol. ‒ 2019. ‒ V. 858. ‒ P. 172467. 10.1016/j.ejphar.2019.172467.
  16. Che F., Liu Y., Xu C. Prevention and treatment of doxorubicin-induced cardiotoxicity by dexrazoxane and schisandrin B in rabbits // Int J Toxicol. ‒ 2011. ‒ V. 30, № 6. ‒ P. 681-9. 10.1177/1091581811415873.
  17. Lai R. C., Wang X. D., Zhang X., Lin W. Q., Rong T. H. Heart fatty acid-binding protein may not be an early biomarker for anthracycline-induced cardiotoxicity in rabbits // Med Oncol. ‒ 2012. ‒ V. 29, № 3. ‒ P. 2303-8. 10.1007/s12032-011-9843-x.
  18. Gava F. N., Zacché E., Ortiz E. M., Champion T., Bandarra M. B., Vasconcelos R. O., Barbosa J. C., Camacho A. A. Doxorubicin induced dilated cardiomyopathy in a rabbit model: an update // Res Vet Sci. ‒ 2013. ‒ V. 94, № 1. ‒ P. 115-21. 10.1016/j.rvsc.2012.07.027.
  19. European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. European Treaty Series - No. 123. – 1896: 11.
  20. Afsar T., Razak S., Batoo K. M., Khan M. R. Acacia hydaspica R. Parker prevents doxorubicin-induced cardiac injury by attenuation of oxidative stress and structural Cardiomyocyte alterations in rats // BMC Complement Altern Med. ‒ 2017. ‒ V. 17, № 1. ‒ P. 554. 10.1186/s12906-017-2061-0.
  21. Du Q., Zhu B., Zhai Q., Yu B. Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3 // Am J Transl Res. ‒ 2017. ‒ V. 9, № 7. ‒ P. 3360-3373.
  22. Pozharitskaya O. N., Shikov A. N., Laakso I., Seppänen-Laakso T., Makarenko I. E., Faustova N. M., Makrova M. N., Makarov V. G. Bioactivity and chemical characterization of gonads of green sea urchin Strongylocentrotus droebachiensis from Barents Sea // Journal of Functional Foods. ‒ 2015. ‒ V. 17. ‒ P. 227-234. 10.1016/j.jff.2015.05.030.
  23. Андреева А. И., Кожемякин Н. А., Кишкун А. А. Модификация определения перекисей липидов в тесте с тиобарбитуровой кислотой // Лабораторное дело. ‒ 1988. ‒ V. 11. ‒ P. 41-43.
  24. Медицинские лабораторные технологии. Справочник/ Под ред. Карпищенко А. И. СПб: Интермедика, 2002. - 600 стр. - С. 68 – 69
  25. Гущин Я. А., Мужикян А. А. Влияние фиксирующих жидкостей на микроскопическую структуру органов мелких лабораторных животных // Международный вестник ветеринарии. ‒ 2014. ‒ V. 3. ‒ P. 88-95
  26. Мужикян А. А., Макарова М. Н., Гущин Я. А. Особенности гистологической обработки органов и тканей лабораторных животных // Международный вестник ветеринарии. ‒ 2014. ‒ V. 2. ‒ P. 103-109
  27. Ruben Z. Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse // Guides for Toxicologic Pathology / Ruben Z. et al. Society of Toxicologic Pathology., 2000. ‒ р. 1-10.
  28. Wu R., Yao P. A., Wang H. L., Gao Y., Yu H. L., Wang L., Cui X. H., Xu X., Gao J. P. Effect of fermented Cordyceps sinensis on doxorubicin‑induced cardiotoxicity in rats // Mol Med Rep. ‒ 2018. ‒ V. 18, № 3. ‒ P. 3229-3241. 10.3892/mmr.2018.9310.
  29. Saad S. Y., Najjar T. A., Alashari M. Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration // J Biochem Mol Toxicol. ‒ 2004. ‒ V. 18, № 2. ‒ P. 78-86. 10.1002/jbt.20012.
  30. El-Agamy D. S., El-Harbi K. M., Khoshhal S., Ahmed N., Elkablawy M. A., Shaaban A. A., Abo-Haded H. M. Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways // Cancer Manag Res. ‒ 2019. ‒ V. 11. ‒ P. 47-61. 10.2147/cmar.s186696.
  31. Takemura G., Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management // Prog Cardiovasc Dis. ‒ 2007. ‒ V. 49, № 5. ‒ P. 330-52. 10.1016/j.pcad.2006.10.002.
  32. Green P. S., Leeuwenburgh C. Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis // Biochim Biophys Acta. ‒ 2002. ‒ V. 1588, № 1. ‒ P. 94-101. 10.1016/s0925-4439(02)00144-8.

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