Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 2, pp 343–349 | Cite as

Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model

  • Ping Xiang
  • Hai Yan Deng
  • Karen Li
  • Guo-Ying Huang
  • Yuan Chen
  • Liu Tu
  • Pak Cheung Ng
  • Nga Hin Pong
  • Hailu Zhao
  • Lei Zhang
  • Rita Yn Tz Sung
Original Article



Dexrazoxane (DZR), a clinically approved cation chelator, is effective in reducing doxorubicin (DOX)-induced heart damage, yet its cardioprotective mechanism is not fully understood. We aimed to investigate the effects of DZR on the activation of Akt and Erk 1/2 signals in a rat model of DOX-induced cardiomyopathy.


Male Sprague–Dawley rats received weekly DOX injection (2.5 mg/kg) for 6 weeks, with or without DZR pretreatment at a dose ratio of 20:1. The ventricular functions of these animals were monitored at week 6, 9 and 11 by echocardiography. At week 11, their heart morphology was studied by light and electron microscopy. Phosphorylation of Akt and Erk in heart tissues was measured by Western blot analysis.


DOX caused myocardial damage with compromised left ventricular function, increased myocardium injury and reduced phosphorylation of Akt and Erk. DZR exerted a significant cardioprotective effect in terms of improved fractional shortening, cardiac output and cardiomyopathy score at one or more time points. We also provided the first evidence that dexarazoxane-treated animals had increased levels of Akt and Erk activation, whilst total Akt and Erk remained unchanged.


Our results showed that the cardioprotective effect of dexarazoxane has been sustained beyond the treatment period. The data also suggested that activation of the Akt and Erk signaling pathways was regulated in the course of DOX-induced cardiomyopathy and protection by DZR.


Dexrazoxane Doxorubicin Cardioprotection Akt Erk1/2 



This research project was support by Li Ka Shing Institute of Health Sciences Grant, The Chinese University of Hong Kong (Project ID: 6901985), and Earmarked Grant, Research Grants Council, Hong Kong Special Administrative Region (Project No. CUHK4521/05M).


  1. 1.
    Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C (2002) Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 62:4592–4598PubMedGoogle Scholar
  2. 2.
    Clerk A, Cole SM, Cullingford TE, Harrison JG, Jormakka M, Valks DM (2003) Regulation of cardiac myocyte cell death. Pharmacol Ther 97:223–261PubMedCrossRefGoogle Scholar
  3. 3.
    Gabrielson K, Bedja D, Pin S, Tsao A, Gama L, Yuan B, Muratore N (2007) Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury. Cancer Res 67:1436–1441PubMedCrossRefGoogle Scholar
  4. 4.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRefGoogle Scholar
  5. 5.
    González A, Ravassa S, Loperena I, Lopez B, Beaumont J, Querejeta R, Larman M, Diez J (2007) Association of depressed cardiac gp130-mediated antiapoptotic pathways with stimulated cardiomyocyte apoptosis in hypertensive patients with heart failure. J Hypertens 25:2148–2157PubMedCrossRefGoogle Scholar
  6. 6.
    Grauslund M, Thougaard AV, Fuchtbauer A, Hofland KF, Hjorth PH, Jensen PB, Sehested M, Fuchtbauer EM, Jensen LH (2007) A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIalpha in vivo. Mol Pharmacol 72:1003–1014PubMedCrossRefGoogle Scholar
  7. 7.
    Hasinoff BB, Herman EH (2007) Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol 7:140–144PubMedCrossRefGoogle Scholar
  8. 8.
    Hausenloy DJ, Yellon DM (2003) The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 35:339–341PubMedCrossRefGoogle Scholar
  9. 9.
    Hausenloy DJ, Yellon DM (2004) New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 61:448–460PubMedCrossRefGoogle Scholar
  10. 10.
    Héon S, Bernier M, Servant N, Dostanic S, Wang C, Kirby GM, Alpert L, Chalifour LE (2003) Dexrazoxane does not pretect against doxorubicin-induced damage in young rats. Am J Physiol Heart Circ Physiol 285:H499–H505PubMedGoogle Scholar
  11. 11.
    Hou XW, Son J, Wang Y, Ru YX, Lian Q, Majiti W, Amazouzi A, Zhou YL, Wang PX, Han ZC (2006) Granulocyte colony-stimulating factor reduces cardiomyocyte apoptosis and improves cardiac function in adriamycin-induced cardiomyopathy in rats. Cardiovasc Drugs Ther 20:85–91PubMedCrossRefGoogle Scholar
  12. 12.
    Imondi AR, Della Torre P, Mazue G, Sullivan TM, Robbins TL, Hagerman LM, Podesta A, Pinciroli G (1996) Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs. Cancer Res 56:4200–4204PubMedGoogle Scholar
  13. 13.
    Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H (1990) Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol Ther 47:219–231PubMedCrossRefGoogle Scholar
  14. 14.
    Kluza J, Marchetti P, Gallego MA, Lancel S, Fournier C, Loyens A, Beauvillain JC, Bailly C (2004) Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene 23:7018–7030PubMedCrossRefGoogle Scholar
  15. 15.
    Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Walker UA (2007) Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 151:771–778PubMedCrossRefGoogle Scholar
  16. 16.
    Li K, Sung RY, Huang WZ, Yang M, Pong NH, Lee SM, Chan WY, Zhao H, To MY, Fok TF, Li CK, Wong YO, Ng PC (2006) Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation 113:2211–2220PubMedCrossRefGoogle Scholar
  17. 17.
    Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, Kanamori H, Khai NC, Maruyama R, Ogino A, Minatoguchi S, Fujiwara T, Fujiwara H (2006) Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation 113:535–543PubMedCrossRefGoogle Scholar
  18. 18.
    Lou H, Danelisen I, Singal PK (2005) Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 288:H1925–H1930PubMedCrossRefGoogle Scholar
  19. 19.
    Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF (2007) Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 67:8839–8846PubMedCrossRefGoogle Scholar
  20. 20.
    Marty M, Espie M, Llombart A, Monnier A, Rapoport BL, Stahalova V (2006) Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17:614–622PubMedCrossRefGoogle Scholar
  21. 21.
    Myer C (1998) The role of iron in doxorubicin-induced cardiomyopathy. Semin Oncol 25:10–14Google Scholar
  22. 22.
    Negoro S, Oh H, Tone E, Kunisada K, Fujio Y, Walsh K, Kishimoto T, Yamauchi-Takihara K (2001) Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase–3 interaction. Circulation 103:555–561PubMedGoogle Scholar
  23. 23.
    Nozaki N, Shishido T, Takeishi Y, Kubota I (2004) Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 110:2869–2874PubMedCrossRefGoogle Scholar
  24. 24.
    Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905PubMedCrossRefGoogle Scholar
  25. 25.
    Su HF, Samsamshariat A, Fu J, Shan YX, Chen YH, Piomelli D, Wang PH (2006) Oleylethanolamide activates Ras-Erk pathway and improves myocardial function in doxorubicin-induced heart failure. Endocrinology 147:827–834PubMedCrossRefGoogle Scholar
  26. 26.
    Sugden PH (2003) Ras, Akt, and mechanotransduction in the cardiac myocyte. Circ Res 93:1179–1192PubMedCrossRefGoogle Scholar
  27. 27.
    Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S, Kalyanaraman B (2004) Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms. intermediacy of H(2) O(2)- and p53-dependent pathways. J Biol Chem 279:25535–25543PubMedCrossRefGoogle Scholar
  28. 28.
    Wang Y (2007) Mitogen-activated protein kinases in heart development and diseases. Circulation 116:1413–1423PubMedCrossRefGoogle Scholar
  29. 29.
    Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang J, Clark JR Jr, Herman EH, Ferrans VJ (1996) Doxorubicin-induced apoptosis in spontaneously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187. J Mol Cell Cardiol 28:1931–1943PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ping Xiang
    • 1
  • Hai Yan Deng
    • 2
  • Karen Li
    • 3
  • Guo-Ying Huang
    • 2
  • Yuan Chen
    • 1
  • Liu Tu
    • 4
  • Pak Cheung Ng
    • 3
  • Nga Hin Pong
    • 3
  • Hailu Zhao
    • 5
  • Lei Zhang
    • 3
  • Rita Yn Tz Sung
    • 3
    • 6
  1. 1.Department of CardiologyChildren’s Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of CardiologyChildren’s Hospital of Fudan UniversityShanghaiChina
  3. 3.Li Ka Shing Institute of Health Sciences, Department of PaediatricsThe Chinese University of Hong KongShatinHong Kong
  4. 4.Department of PhysiologyChongqing Medical UniversityChongqingChina
  5. 5.Department of Medicine and TherapeuticsThe Chinese University of Hong KongShatinHong Kong
  6. 6.Department of PaediatricsThe Chinese University of Hong Kong, The Prince of Wales HospitalShatin, NTHong Kong

Personalised recommendations