Skip to main content

Comparision of doxorubicin-induced cardiotoxicity in the ICR mice of different sources

Abstract

Doxorubicin is a widely used chemotherapeutic agents and is now part of standard therapeutic regimens for a variety of cancers (eg, hematopoietic malignancies and advanced solid tumors of the breast, ovary, thyroid, and bone). However, a potentially lethal and dose-dependent cardiotoxicity that appears within a short time after treatment limits the usage of doxorubicin in cancer patients. Although the mechanism of doxorubicin-induced cardiotoxicity is not completely understood, it is thought that free radical-induced oxidative stress and excessive production of reactive oxygen species are primary drivers of its toxicity. In this study, we compared the doxorubicin-induced cardiotoxicity of ICR mice obtained from three different sources and evaluated the utility of Korl:ICR stock established by the Korean FDA. Because doxorubicin-induced cardiotoxicity is thought to involve the excessive generation of ROS followed by oxidative stress, we determined the representative tissue index of oxidation, lipid peroxidation, and antioxidant, glutathione (GSH), as well as the parameters of heart injury. Doxorubicin treatment successfully induced cardiotoxicity as evidenced by histological examination and serum parameters (eg, levels of LDH and CK activities) in ICR mice. It was accompanied by increased lipid peroxidation and a decrease in both cysteine and GSH, further supporting previous reports that oxidative stress is a potential mechanism of doxorubicin-induced cardiotoxicity. Of interest, we did not observe a significant difference in doxorubicin-induced cardiotoxicity among mice of different origins. Collectively, our results suggest that Korl:ICR strain may be useful in the research of doxorubicin-induced cardiotoxicity.

References

  1. Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014; 63(25): 2751–2768.

    Article  Google Scholar 

  2. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004; 56(2): 185–229.

    Article  CAS  Google Scholar 

  3. Perrino C, Schiattarella GG, Magliulo F, Ilardi F, Carotenuto G, Gargiulo G, Serino F, Ferrone M, Scudiero F, Carbone A, Trimarco B, Esposito G. Cardiac side effects of chemotherapy: state of art and strategies for a correct management. Curr Vasc Pharmacol 2014; 12(1): 106–116.

    Article  CAS  Google Scholar 

  4. Raschi E, Vasina V, Ursino MG, Boriani G, Martoni A, De Ponti F. Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy. Pharmacol Ther 2010; 125(2): 196–218.

    Article  CAS  Google Scholar 

  5. Carter SK. Adriamycin-Review. J Natl Cancer Inst 1975; 55(6): 1265–1274.

    Article  CAS  Google Scholar 

  6. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin Cardiomyopathy-Evaluation by Phonocardiography, Endomyocardial Biopsy, and Cardiac-Catheterization. Ann Intern Med 1978; 88(2): 168–175.

    Article  CAS  Google Scholar 

  7. Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC. Early Anthracycline Cardiotoxicity. Am J Med 1978; 65(5): 823–832.

    Article  CAS  Google Scholar 

  8. Maksimenko AV, Vavaev AV. Antioxidant enzymes as potential targets in cardioprotection and treatment of cardiovascular diseases. Enzyme antioxidants: the next stage of pharmacological counterwork to the oxidative stress. Heart Int 2012; 7(1): e3.

    Article  Google Scholar 

  9. Todorova VK, Beggs ML, Delongchamp RR, Dhakal I, Makhoul I, Wei JY, Klimberg VS. Transcriptome profiling of peripheral blood cells identifies potential biomarkers for doxorubicin cardiotoxicity in a rat model. PLoS One 2012; 7(11): e48398.

    Article  CAS  Google Scholar 

  10. Sterba M, Popelova O, Vavrova A, Jirkovsky E, Kovarikova P, Gersl V, Simunek T. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 2013; 18(8): 899–929.

    Article  CAS  Google Scholar 

  11. Thayer WS. Adriamycin Stimulated Superoxide Formation in Sub-Mitochondrial Particles. Chem Biol Interact 1977; 19(3): 265–278.

    Article  CAS  Google Scholar 

  12. Doroshow JH, Reeves J. Anthracycline-Enhanced Oxygen Radical Formation in the Heart. in: Proc Am Assoc Canc Res 1980; 21: 266.

    Google Scholar 

  13. Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ. Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 2014; 34(1): 106–135.

    Article  CAS  Google Scholar 

  14. Chia R, Achilli F, Festing MF, Fisher EM. The origins and uses of mouse outbred stocks. Nat Genet 2005; 37(11): 1181–1186.

    Article  CAS  Google Scholar 

  15. Nolin TD, McMenamin ME, Himmelfarb J. Simultaneous determination of total homocysteine, cysteine, cysteinylglycine, and glutathione in human plasma by high-performance liquid chromatography: application to studies of oxidative stress. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852(1-2): 554–561.

    Article  CAS  Google Scholar 

  16. Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977; 197(4299): 165–167.

    Article  CAS  Google Scholar 

  17. Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013; 1830(5): 3143–3153.

    Article  CAS  Google Scholar 

  18. Jung YS, Kim SJ, Kwon DY, Kim YC. Comparison of the effects of buthioninesulfoximine and phorone on the metabolism of sulfur-containing amino acids in rat liver. Biochem Biophys Res Commun 2008; 368(4): 913–918.

    Article  CAS  Google Scholar 

  19. Doroshow JH, Locker GY, Baldinger J, Myers CE. The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 1979; 26(2): 285–295.

    CAS  PubMed  Google Scholar 

  20. Indu R, Azhar TS, Nair A, Nair CK. Amelioration of doxorubicin induced cardio-and hepato-toxicity by carotenoids. J Cancer Res Ther 2014; 10(1): 62–67.

    Article  CAS  Google Scholar 

  21. Shin HJ, Cho YM, Shin HJ, Kim HD, Choi KM, Kim MG, Shin HD, Chung MW. Comparison of commonly used ICR stocks and the characterization of Korl:ICR. Lab Anim Res 2017; 33(1): 8–14.

    Article  Google Scholar 

  22. Tan G, Lou Z, Liao W, Zhu Z, Dong X, Zhang W, Li W, Chai Y. Potential biomarkers in mouse myocardium of doxorubicin-induced cardiomyopathy: a metabonomic method and its application. PLoS One 2011; 6(11): e27683.

    Article  CAS  Google Scholar 

  23. Liu X, Chen Z, Chua CC, Ma YS, Youngberg GA, Hamdy R, Chua BH. Melatonin as an effective protector against doxorubicin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 2002; 283(1): H254–263.

    Article  CAS  Google Scholar 

  24. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 2005; 111(13): 1601–1610.

    Article  CAS  Google Scholar 

  25. Ma Y, Zhang X, Bao H, Mi S, Cai W, Yan H, Wang Q, Wang Z, Yan J, Fan GC et al. Toll-like receptor (TLR) 2 and TLR4 differentially regulate doxorubicin induced cardiomyopathy in mice. PLoS One 2012; 7(7): e40763.

    Article  CAS  Google Scholar 

  26. Thayer WS. Adriamycin stimulated superoxide formation in submitochondrial particles. Chem Biol Interact 1977; 19(3): 265–278.

    Article  CAS  Google Scholar 

  27. Doroshow JH, Locker GY, Ifrim I, Myers CE. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J Clin Invest 1981; 68(4): 1053–1064.

    Article  CAS  Google Scholar 

  28. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 1980; 65(1): 128–135.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This project was supported by a grant of BIOREIN (Laboratory Animal Bio Resources Initiative) from Ministry of Food and Drug Safety in 2016.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Young-Suk Jung.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S.H., Kim, KJ., Kim, JH. et al. Comparision of doxorubicin-induced cardiotoxicity in the ICR mice of different sources. Lab Anim Res 33, 165–170 (2017). https://doi.org/10.5625/lar.2017.33.2.165

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.5625/lar.2017.33.2.165

Keywords