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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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Dexrazoxane Doxorubicin Cardioprotection Akt Erk1/2 

Notes

Acknowledgments

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).

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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

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