Cardiovascular Toxicology

, Volume 12, Issue 4, pp 341–349 | Cite as

Resveratrol Attenuates Doxorubicin-Induced Cardiomyocyte Apoptosis in Lymphoma Nude Mice by Heme Oxygenase-1 Induction

  • Jun Gu
  • Zhi-ping Song
  • Dong-mei Gui
  • Wei Hu
  • Yue-guang Chen
  • Da-dong Zhang


Doxorubicin (DOX) has been used in a variety of human malignancies for decades, in particular of lymphoma. But increased cardiomyocyte apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) generates cardiovascular protective effects by heme oxygenase-1(HO-1)-mediated mechanism. The present study was designed to determine whether RES protected cardiomyocyte against apoptosis through induction of HO-1 in lymphoma nude mouse in vivo. After being developed into lymphoma model, 40 male Balb/c nude mice were randomized to one of the following four treatments (10 mice per group): control, DOX, DOX + RES and DOX + RES + HO-1 inhibitor (zinc protoporphyrin IX, ZnPP). The results showed that DOX injection markedly decreased the body weight, the heart weight and the ratio of heart weight to body weight, but inversely increased cardiomyocyte apoptosis and the level of serum lactate dehydrogenase and creatine kinase. Moreover, DOX injection attenuated HO-1 expression and enzymatic activity as well as increased P53 expression, modulated Bcl-2/Bax expression and enhanced caspase 3 activity. These cardiotoxic effects of DOX were ameliorated by its combination with RES. However, the protective effects of RES were reversed by the addition of ZnPP. Taken together, it is concluded that HO-1 plays a core role for protective action of RES in DOX-induced cardiomyocyte apoptosis in lymphoma nude mice.


Resveratrol Doxorubicin Cardiotoxicity Apoptosis Heme oxygenase-1 



This study was supported by grant 2008Y052 from Youth foundation of Shanghai Municipal Health Bureau (Shanghai, China).

Conflict of interest

The authors have no financial and/or personal relationships with other people or organization that could influence this report.


  1. 1.
    Wouters, K. A., Kremer, L. C., Miller, T. L., Herman, E. H., & Lipshultz, S. E. (2005). Protecting against anthracycline induced myocardial damage: A review of the most promising strategies. British Journal of Haematology, 131, 561–578.PubMedCrossRefGoogle Scholar
  2. 2.
    Gianni, L., Herman, E. H., Lipshultz, S. E., Minotti, G., Sarvazyan, N., & Sawyer, D. B. (2008). Anthracycline cardiotoxicity: From bench to bedside. Journal of Clinical Oncology, 26, 3777–3784.PubMedCrossRefGoogle Scholar
  3. 3.
    Limat, S., Demesmay, K., Voillat, L., Bernard, Y., Deconinck, E., Brion, A., et al. (2003). Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma. Annal of Oncology, 14, 277–281.CrossRefGoogle Scholar
  4. 4.
    Aviles, A., Arevila, N., Diaz Maqueo, J. C., Gómez, T., García, R., & Nambo, M. J. (1993). Late cardiac toxicity of doxorubicin, epirubicin, and mitoxantrone therapy for Hodgkin’s disease in adults. Leukemia & Lymphoma, 11, 275–279.CrossRefGoogle Scholar
  5. 5.
    Haddy, T. B., Adde, M. A., McCalla, J., Domanski, M. J., Datiles, M, 3rd, Meehan, S. C., et al. (1998). Late effects in long-term survivors of high-grade non-Hodgkin’s lymphomas. Journal of Clinical Oncology, 16, 2070–2079.PubMedGoogle Scholar
  6. 6.
    Hequet, O., Le, Q. H., Moullet, I., Pauli, E., Salles, G., Espinouse, D., et al. (2004). Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. Journal of Clinical Oncology, 22, 1864–1871.PubMedCrossRefGoogle Scholar
  7. 7.
    Limat, S., Demesmay, K., Voillat, L., Bernard, Y., Deconinck, E., Brion, A., et al. (2003). Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma. Annal of Oncology, 14, 277–281.CrossRefGoogle Scholar
  8. 8.
    Bernuzzi, F., Recalcati, S., Alberghini, A., & Cairo, G. (2009). Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes: Role for heme oxygenase-1 down-modulation. Chemico-Biological Interactions, 177, 12–20.PubMedCrossRefGoogle Scholar
  9. 9.
    Delmas, D., Jannin, B., & Latruffe, N. (2005). Resveratrol: preventing properties against vascular alterations and ageing. Molecular Nutrition & Food Research, 49, 377–395.CrossRefGoogle Scholar
  10. 10.
    Kim, J. W., Lim, S. C., Lee, M. Y., Lee, J. W., Oh, W. K., Kim, S. K., et al. (2010). Inhibition of neointimal formation by trans-resveratrol: Role of phosphatidyl inositol 3-kinase-dependent Nrf2 activation in heme oxygenase-1 induction. Molecular Nutrition & Food Research, 54, 1497–1505.CrossRefGoogle Scholar
  11. 11.
    Zhang, C., Feng, Y., Qu, S., Wei, X., Zhu, H., Luo, Q., et al. (2011). Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovascular Research, 90, 538–545.PubMedCrossRefGoogle Scholar
  12. 12.
    Oktem, G., Uysal, A., Oral, O., Sezer, E. D., Olukman, M., Erol, A., et al. (2012). Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Experiment and Toxicologic Pathology, 64, 471–479.CrossRefGoogle Scholar
  13. 13.
    Lopes de Menezes, D. E., Denis-Mize, K., Tang, Y., Ye, H., Kunich, J. C., Garrett, E. N., et al. (2007). Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma. Journal of Immunotherapy, 30, 64–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee, Y. S., Kang, Y. J., Kim, H. J., Park, M. K., Seo, H. G., Lee, J. H., et al. (2006). Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. Apoptosis, 11, 1091–1100.PubMedCrossRefGoogle Scholar
  15. 15.
    Li, S. Y., Gomelsky, M., Duan, J., Zhang, Z., Gomelsky, L., Zhang, X., et al. (2004). Overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene prevents acetaldehyde-induced cell injury in human umbilical vein endothelial cells: role of ERK and p38 mitogen-activated protein kinase. The Journal of Biological Chemistry, 279, 11244–112452.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou, S., Starkov, A., Froberg, M. K., Leino, R. L., & Wallace, K. B. (2001). Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Research, 61, 771–777.PubMedGoogle Scholar
  17. 17.
    Childs, A. C., Phaneuf, S. L., Dirks, A. J., Phillips, T., & Leeuwenburgh, C. (2002). Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis as well as increased mitochondrial efficiency, superoxid dismutase activity, and Bcl-2:Bax ratio. Cancer Research, 62, 4592–4598.PubMedGoogle Scholar
  18. 18.
    Ryter, S. W., Alam, J., & Choi, A. M. (2006). Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological Reviews, 86, 583–650.PubMedCrossRefGoogle Scholar
  19. 19.
    Kim, H. P., Ryter, S. W., & Choi, A. M. (2006). CO as a cellular signaling molecule. Annual Review of Pharmacology Toxicology, 46, 411–449.CrossRefGoogle Scholar
  20. 20.
    Ollinger, R., Wang, H., Yamashita, K., Wegiel, B., Thomas, M., Margreiter, R., et al. (2007). Therapeutic applications of bilirubin and biliverdin in transplantation. Antioxidants & Redox Signaling, 9, 2175–2185.CrossRefGoogle Scholar
  21. 21.
    Wang, G., Hamid, T., Keith, R. J., Zhou, G., Partridge, C. R., Xiang, X., et al. (2010). Cardioprotective and anti-apoptotic effects of heme oxygenase-1 in the failing heart. Circulation, 121, 1912–1925.PubMedCrossRefGoogle Scholar
  22. 22.
    Sun, M. H., Pang, J. H., Chen, S. L., Han, W. H., Ho, T. C., Chen, K. J., et al. (2010). Retinal protection from acute glaucoma-induced ischemia-reperfusion injury through pharmacologic induction of heme oxygenase-1. Investigative Ophthalmology & Visual Science, 51, 4798–4808.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jun Gu
    • 1
  • Zhi-ping Song
    • 1
  • Dong-mei Gui
    • 1
  • Wei Hu
    • 1
  • Yue-guang Chen
    • 1
  • Da-dong Zhang
    • 1
  1. 1.Department of Cardiology, Minhang Hospital, Ruijin Hospital GroupShanghai Jiaotong University School of MedicineShanghaiPeople’s Republic of China

Personalised recommendations