Cell Biology and Toxicology

, Volume 24, Issue 1, pp 63–73

The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats

Article

Abstract

The therapeutic value of doxorubicin as an effective antineoplastic agent is limited by its cardiotoxic side-effects. The administration of doxorubicin (10 mg/kg) to male Wistar rats induced necrosis and apoptosis in heart tissues. It also caused oxidative stress damage as evidenced by the elevation of malondialdehyde and protein carbonyl levels and catalase activity, accompanied by the concurrent depletion of total antioxidant capacity and of superoxide dismutase level in cardiac tissues. The doxorubicin-induced cardiotoxicity and oxidative stress damage were also accompanied by increases of myeloperoxidase activity, total calcium content, and the expression of Bcl-2 protein in heart tissues. Most of these doxorubicin-induced biochemical and histological alterations were effectively attenuated by prior administration of purified standardized extract (1.5% withanolides; manufactured by Idea Sphere Inc., American Fork, UT, USA) of Withania somnifera (300 mg/kg). Thus, Withania may play a role in the protection against cardiotoxicity and thus might be a useful adjuvant therapy where doxorubicin is the cancer-treating drug.

Keywords

Doxorubicin Cardiotoxicity Protection Withania Apoptosis 

Abbreviations

AST

aspartate aminotransferase

CAT

Catalase

DXR

Doxorubicin

FRAP

ferric reducing antioxidant power

LP

lipid peroxidation

MDA

Malondialdehyde

MPO

Myeloperoxidase

ROS

reactive oxygen species

SOD

superoxide dismutase

TAC

total antioxidant capacity

TBA

thiobarbituric acid

TUNEL

terminal deoxynucleotidyl transferase mediated dUTP nick end labelling

WIT

Withania somnifera Dunal

References

  1. Abdel-Wahab MH, El-Mahdy MA, Abd-Ellah MF, Helat GK, Khalifa F, Hamada FMA. Influence of p-coumaric acid on doxorubicin-induced oxidative stress in rat heart. Pharmacol Res 2003;48:461–5.PubMedCrossRefGoogle Scholar
  2. Aebi H. Catalase. Methods Enzymol 1984;105:121–6.PubMedGoogle Scholar
  3. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of (antioxidant power): The FRAP assay. Anal Biochem 1996;293:70–6.CrossRefGoogle Scholar
  4. Chaurasia SS, Panda S, Kar A. Withania somnifera root extracts in the regulation of lead-induced oxidative damage in male mouse. Pharmacol Res 2000;41:663–6.PubMedCrossRefGoogle Scholar
  5. Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C. 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 2002;62:4592–8.PubMedGoogle Scholar
  6. Choudhary MI, Nawaz SA, ul-Haq Z, et al. Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem Biophys Res Commun 2005;334:276–87.PubMedCrossRefGoogle Scholar
  7. Dalloz F, Maingon P, Cottin Y, Briot F, Horiot JC, Rochette L. Effect of combined irradiation and doxorubicin treatment on cardiac function and antioxidant defenses in the rat. Free Radic Biol Med 1999;26:785–800.PubMedCrossRefGoogle Scholar
  8. Davis L, Kuttan G. Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice. J Ethnopharmacol 1998;62:209–14.PubMedCrossRefGoogle Scholar
  9. Davis L, Kuttan G. Effect of Withania somnifera on cyclophosphamide-induced urotoxicity. Cancer Lett 2000;148:9–17.PubMedCrossRefGoogle Scholar
  10. Dhuley JN. Adaptogenic and cardioprotective action of ashwagandha in rats and frogs. J Ethnopharmacol 2000;70:57–63.PubMedCrossRefGoogle Scholar
  11. Ermak G, Davies KJA. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol 2001;38:713–21.CrossRefGoogle Scholar
  12. Fujimura L, Matsudo Y, Kang M, Takamori Y, Tokuhisa T, Hatano M. Protective role of Nd1 in doxorubicin-induced cardiotoxicity. Cardiovasc Res 2004;64:315–21.PubMedCrossRefGoogle Scholar
  13. Gille L, Nohl H. Analyses of the molecular mechanism of adriamycin-induced cardiotoxicity. Free Radic Biol Med 1997;23:775–82.PubMedCrossRefGoogle Scholar
  14. Gupta SK, Dua A, Vohra BP. Withania somnifera (Ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications. Drug Metab Drug Interact 2003;19:211–22.Google Scholar
  15. Hillegas LM, Griswold DE, Brickson B, Albrightson-Winslow C. Assessment of myloperoxidase activity in whole rat kidney. J Pharmacol Methods 1990;24:285–95.CrossRefGoogle Scholar
  16. Jang YM, Kendaiah S, Drew B, et al. Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett 2004;577:483–90.PubMedCrossRefGoogle Scholar
  17. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000;7:153–63.PubMedCrossRefGoogle Scholar
  18. Klebanoff SJ. Myloperoxidase. Proc Assoc Am Physicians 1999;111:383–9.PubMedGoogle Scholar
  19. Minotti G, Parlani M, Salvatorelli E, et al. Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue. Br J Pharmacol 2001;134(6):1271–8.PubMedCrossRefGoogle Scholar
  20. Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 2000;5:334–46.PubMedGoogle Scholar
  21. Mizutani H, Tada-Oikawa S, Hiraku Y, Kojima M, Kawanishi S. Mehanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci 2005;76:1439–53.PubMedCrossRefGoogle Scholar
  22. Mohanty I, Arya DS, Dinda A, Talwar KK, Joshi S, Gupta SK. Mechanisms of cardioprotective effect of Withania somnifera in experimentally induced myocardial infraction. Basic Clin Pharmacol Toxicol 2004;94:184–90.PubMedGoogle Scholar
  23. Mukherjee S, Banerjee SK, Maulik M, Dinda AK, Maulik KS. Protection against acute adriamycin-induced cardiotoxicity by garlic endogenous antioxidants and inhibition of TNF-alpha expression. BMC Pharmacol 2003;3:1–9.CrossRefGoogle Scholar
  24. Nicholls S, Hazen SL. Myloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005;25:274–8.Google Scholar
  25. Oliveira PJ, Bjork JA, Santos MS, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 2004;200:159–68.PubMedCrossRefGoogle Scholar
  26. Padmavathi B, Rath PC, Rao AR, Singh RP. Roots of Withania somnifera inhibit forestomach and skin carcinogenesis in mice. eCAM 2005;2:99–105.PubMedGoogle Scholar
  27. Peterson GL. A simplification of the protein assay method of Lowry et al which is more generally applicable. Anal Biochem 1977;83:346–56.PubMedCrossRefGoogle Scholar
  28. Rasool M, Varalakshmi P. Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: An in vivo and in vitro study. Vascul Pharmacol 2006;44:406–10.PubMedCrossRefGoogle Scholar
  29. Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 1994;233:357–63.PubMedCrossRefGoogle Scholar
  30. Scartezzini P, Speroni E. Review on some plants of Indian traditional medicine with antioxidant activity. J Ethnopharmacol 2000;71, 23–43.PubMedCrossRefGoogle Scholar
  31. Sorg O. Oxidative stress: a theoretical model for a biological reality. Comptes Rendus Biol 2004;327:649–62.CrossRefGoogle Scholar
  32. Sun M, Zigman S. An improved spectrophotometric assay for superoxide dismutase based on epinephrine autoxidation. Anal Biochem 1978;247:81–9.CrossRefGoogle Scholar
  33. Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978;86:271–8.PubMedCrossRefGoogle Scholar
  34. Waring P. Redox active calcium ion channels and cell death. Arch Biochem Biophys 2005;434:33–42.PubMedCrossRefGoogle Scholar
  35. Yagmurca M, Fadillioglu E, Erdogan H, Ucar M, Sogut S, Irmak MK. Erdosterine prevents doxorubicin-induced cardiotoxicity. Pharmacol Res 2003;48:377–82.PubMedCrossRefGoogle Scholar
  36. Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S. Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology 2006;218:164–71.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  1. 1.Biology Department, College of ScienceU.A.E. UniversityAl-AinUnited Arab Emirates
  2. 2.Department of PathologyTwam HospitalAl-AinUnited Arab Emirates
  3. 3.Biology DepartmentU.A.E. UniversityAl-AinUnited Arab Emirates

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