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

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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.

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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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Authors and Affiliations

  1. Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Ping Xiang & Yuan Chen

  2. Department of Cardiology, Children’s Hospital of Fudan University, Shanghai, China

    Hai Yan Deng & Guo-Ying Huang

  3. Li Ka Shing Institute of Health Sciences, Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Karen Li, Pak Cheung Ng, Nga Hin Pong, Lei Zhang & Rita Yn Tz Sung

  4. Department of Physiology, Chongqing Medical University, Chongqing, China

    Liu Tu

  5. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Hailu Zhao

  6. Department of Paediatrics, The Chinese University of Hong Kong, The Prince of Wales Hospital, 6th Floor, Clinical Sciences Block, Shatin, NT, Hong Kong

    Rita Yn Tz Sung

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  1. Ping Xiang
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  2. Hai Yan Deng
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  3. Karen Li
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  5. Yuan Chen
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  6. Liu Tu
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  8. Nga Hin Pong
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  9. Hailu Zhao
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  10. Lei Zhang
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  11. Rita Yn Tz Sung
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Corresponding author

Correspondence to Rita Yn Tz Sung.

Additional information

Ping Xiang and Hai Yan Deng have equal contribution to this study.

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Xiang, P., Deng, H.Y., Li, K. et al. Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model. Cancer Chemother Pharmacol 63, 343–349 (2009). https://doi.org/10.1007/s00280-008-0744-4

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  • DOI: https://doi.org/10.1007/s00280-008-0744-4

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