Grape Seed and Skin Extract Protects Against Acute Chemotherapy Toxicity induced by Doxorubicin in Rat Heart
- 450 Downloads
Doxorubicin (Dox), an antitumor anthracycline antibiotic, plays a key role in the treatment of many neoplastic diseases. However, its chronic administration induces cardiomyopathy. Increased oxidative stress is a major factor implicated in Dox-induced cardiotoxicity. We hypothesized that a pre-treatment with grape seed and skin extract (GSE), commonly used as an antioxidant agent, may alleviate this cardiotoxicity. Rats were treated with GSE (500 mg/kg bw) by intraperitoneal injection during 8 days. On the 4th day, rats were administered a single dose of Dox (20 mg/kg). At the end of the treatment, their hearts were Langendorff-perfused, subjected to ischemia/reperfusion (I/R) injury, and left ventricular functions as heart rate and developed pressure measured. Hearts were also used to determine free iron, H2O2, Ca2+, lipoperoxidation, carbonylation and antioxidant enzymes such as superoxide dismutase (SOD), catalase and peroxidase. Doxorubicin drastically affected heart activity as evidenced after I/R experiments. This effect was associated with an increase in heart free iron and a decrease in Ca2+ concentrations. This effect may have contributed to oxidative stress as assessed by high lipoperoxidation and carbonylation level. GSE counteracted Dox-induced disturbances of hemodynamic parameters, alleviated oxidative stress as assessed by normalized iron and Ca2+ levels and increased SOD activity especially the Mn isoform.
KeywordsDox GSE Heart activity Ca2+ levels SOD CAT POD
We gratefully acknowledge the financial support of the Tunisian Ministry of High Education, Scientific Research and Technology.
- 12.Herskko, C., Link, G., Tzahor, M., Kaltwasser, J. P., Athias, P., Grynberg, A., et al. (1993). Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: studies in rat heart cells in culture. The Journal of Laboratory and Clinical Medicine, 122, 245–251.Google Scholar
- 13.Ishii, K., Tamaoka, A., Takeda, T., Ishii, K., Iwasaki, N., & Shoji, S. (2006). Clinical and neurological features of organoarsenic compound (diphenylarsenic acid) intoxication in Kamisu. Japan Rinsho Shinkeigaku, 46(11), 768. Japanese.Google Scholar
- 17.Kalivendi, S. V., Konorev, E. A., Cunnigham, S., Vanamala, S. K., Kaji, E. H., Joseph, J., et al. (2005). Doxorubicin activates nuclear factor of activated T. lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochemical Journal, 389, 527–539.PubMedCrossRefGoogle Scholar
- 19.Khan, M. F., Wu, X., Tifnis, U. R., Ansari, G. A. S., & Boor, P. J. (2002). Protein adducts of malondialdehyde and 4-hydroxynonemal in livers of iron loaded rats. Quantitation and Localization Toxicology, 173, 193–201.Google Scholar
- 22.Kim, D. S., Kim, H. R., Woo, E. R., et al. (2005). Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular singal-regulated kinase. Biochemical Pharmacology, 70(7), 1066–1078.PubMedCrossRefGoogle Scholar
- 23.Kim, S. Y., Kim, S. J., Kim, B. J., Rah, S. Y., Chung, S. M., Im, M. J., et al. (2006). Doxorubicin induced reactive oxygen species generation and intracellular Ca++ increase are reciprocally modulated in rat cardiomyocytes. Experimental & Molecular Medicine, 38(5), 535–545.Google Scholar
- 28.Li, X. L., Li, B. Y., Gao, H. Q., Cheng, M., Xu, L., Li, X. H., et al. (2009). Proteomics approach to study the mechanism of action of grape seed proanthocyanidin extracts on arterial remodelling in diabetic rats. International Journal of Molecular Medicine, 25, 237–248.Google Scholar
- 30.Misra, H. P., & Fridovich, I. (1972). The generation of superoxide radical during the autoxidation of ferredoxins. Journal of Biological Chemistry, 246(22), 6886–6890.Google Scholar
- 35.Radi, R. (2004). Nitric oxide, oxidants, and protein tyrosine nitration. Proceedings of the National Academy of Sciences of the United States of America, 87, 1620–1624.Google Scholar