Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 6, pp 833–841 | Cite as

6-gingerol ameliorated doxorubicin-induced cardiotoxicity: role of nuclear factor kappa B and protein glycation

  • Wesam M. El-Bakly
  • Manal L. Louka
  • Ali M. El-Halawany
  • Mona F. Schaalan
Original Article

Abstract

Purpose

Doxorubicin is a widely used antitumour drug. Cardiotoxicity is considered a major limitation for its clinical use. The present study was designed to assess the possible antioxidant and antiapoptotic effects of 6-gingerol in attenuating doxorubicin-induced cardiac damage.

Method

Male albino rats were treated with either intraperitoneal doxorubicin (18 mg/kg divided into six equal doses for 2 weeks) and/or oral 6-gingerol (10 mg/kg starting 5 days before and continued till the end of the experiment).

Results

6-gingerol significantly ameliorated the doxorubicin-induced elevation in the cardiac enzymes. The stimulation of oxidative stress by doxorubicin was evidenced by the significant decrease in the serum soluble receptor for advanced glycation endproduct allowing unopposed serum advanced glycation endproduct availability. Moreover, doxorubicin activated nuclear factor kappa B (NF-κB) which was indicated by an increase in its immunohistochemical staining in the nucleus. In addition, doxorubicin-induced cardiotoxicity was accompanied by elevation of cardiac caspase-3. Notably, pretreatment with 6-gingerol significantly ameliorated the changes in sRAGE, NF-κB and cardiac caspase-3. Cardiac enzymes showed significant positive correlation with NF-κB and caspase-3 but negative with serum sRAGE, suggesting their role in doxorubicin-induced cardiac injury. These findings were confirmed by cardiac tissue histopathology.

Conclusion

6-gingerol, a known single compound from ginger with anticancer activity, was shown to have a promising role in cardioprotection against doxorubicin-induced cardiotoxicity. This study suggested a novel mechanism for 6-gingerol cardioprotection, which might be mediated through its antioxidative effect and modulation of NF-κB as well as apoptosis.

Keywords

Doxorubicin (DOX)-cardiotoxicity 6-gingerol Nuclear factor kappa B (NF-κB) Caspase-3 sRAGE (receptor for advanced glycation endproducts) 

Notes

Acknowledgments

Thanks for Dr Ghada Galal for helping in histopathology.

Conflict of interest

None.

References

  1. 1.
    Ayla S, Seckin I, Tanriverdi G et al (2011) Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J Cell Biol 2011:1–9Google Scholar
  2. 2.
    Fadillioğlu E, Erdoğan H, Söğüt S, Kuku I (2003) Protective effects of erdosteine against doxorubicin-induced cardiomyopathy in rats. J Appl Toxicol 23:71–74PubMedCrossRefGoogle Scholar
  3. 3.
    Fan GC, Zhou X, Wang X et al (2008) Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity. Circ Res 103:1270–1279PubMedCrossRefGoogle Scholar
  4. 4.
    Simoncikova P, Ravingerova T, Barancik M (2008) The effect of chronic doxorubicin treatment on mitogen—activated protein kinases and heat stress proteins in rat hearts. Physiol Res 57(2):S97–S102PubMedGoogle Scholar
  5. 5.
    Aiken MJ, Suhag V, Garcia CA et al (2009) Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging. Clin Nucl Med 34(11):762–767PubMedCrossRefGoogle Scholar
  6. 6.
    Li T, Danelisen I, Bello-Klein A, Singal PK (2000) Effects of probucol on changes of antioxidant enzymes in AIC in rats. Cardiovasc Res 46:523–530PubMedCrossRefGoogle Scholar
  7. 7.
    Ferreira ALA, Matsubara LS, Matsubara BB (2008) Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem 6:278–281PubMedCrossRefGoogle Scholar
  8. 8.
    Hudson BI, Bucciarelli LG, Wendt T et al (2003) Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Arch Biochem Biophys 419(1):80–88PubMedCrossRefGoogle Scholar
  9. 9.
    Moriyamaa T, Kemib M, Okumurab C, Yoshiharac K, Horiea T (2010) Involvement of advanced glycation end-products, pentosidine and Nε-(carboxymethyl) lysine, in doxorubicin induced cardiomyopathy in rats. J Toxicol 268:89–97CrossRefGoogle Scholar
  10. 10.
    Arozal W, Watanabe K, Veeraveedu PT, Ma M, Nafrialdi N (2011) Telmisartan inhibits the progression of cardiomyopathy in daunorubicin treated rats: the role of advanced glycation end products. Med J Indones 20:255–262Google Scholar
  11. 11.
    Schmidt AM, Yan SD, Wautier JL, Stern D (1999) Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 84(5):489–497PubMedCrossRefGoogle Scholar
  12. 12.
    Bruynzeel AME, Abou El Hassan MA, Schalkwijk C et al (2007) Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice. BJC 96:937–943PubMedCrossRefGoogle Scholar
  13. 13.
    Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of NF-κB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17PubMedGoogle Scholar
  14. 14.
    Aoki M, Nata T, Morishita R et al (2001) Endothelial apoptosis induced by oxidative stress through activation of NF-κB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 38:48–55PubMedCrossRefGoogle Scholar
  15. 15.
    Joyce D, Bouzahzah B, Fu M et al (1999) Integration of Rac-dependent regulation of cyclin D1 transcription through a NF-κB dependent pathway. J Biol Chem 274:25245–25249PubMedCrossRefGoogle Scholar
  16. 16.
    Injac R, Perse M, Cerne M et al (2009) Protective effects of fullerenol C60(OH)24 against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats with colorectal cancer. Biomaterials 30:1184–1196PubMedCrossRefGoogle Scholar
  17. 17.
    Kolarovic J, Popovic M, Zlinská J, Trivic S, Vojnovic M (2010) Antioxidant activities of celery and parsley juices in rats treated with doxorubicin. Molecules 15:6193–6204PubMedCrossRefGoogle Scholar
  18. 18.
    Seo HB, Lee SC, Kwon TD, Kang JY, Song YJ, Ryu S (2011) The effect of ginger extract ingestion and swimming exercise on insulin resistance and skeletal muscle antioxidant capacity and apoptosis in hyperglycemic rats fed a high-fructose diet. JENB 15(1):41–48Google Scholar
  19. 19.
    Surh Y (1999) Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 428:305–327PubMedCrossRefGoogle Scholar
  20. 20.
    Tjendraputra E, Tran VH, Liu-Brennan D, Roufogalis BD, Duke CC (2001) Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells. Bioorg Chem 29:156–163. It is cited in Aggarwal BB, Shishodia S (2004) Suppression of the NF-κB activation pathway by spice-derived phytochemicals. Ann NY Acad Sci 1030:434–441Google Scholar
  21. 21.
    Oyagbemi AA, Saba AB, Azeez OI (2010) Molecular targets of 6-gingerol: its potential roles in cancer chemoprevention. BioFactors 36:169–178PubMedCrossRefGoogle Scholar
  22. 22.
    Abdel-Aleem S, El-Merzabani MM, Ahmed MS, Taylor DA, Lowe JE (1997) Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. J Mol Cell Cardiol 29:789–797PubMedCrossRefGoogle Scholar
  23. 23.
    Escoubas P, Lajide L, Mizutani J (1995) Termite antifeedant activity in Aframomum activity. Phytochemistry 40:1097–1099CrossRefGoogle Scholar
  24. 24.
    Mansour MA, Bakheet SA, Aleisa AM et al (2008) Protective effect of 6-gingerol against cardiotoxicity induced by doxorubicin. Open Pharmacol J 2:20–23CrossRefGoogle Scholar
  25. 25.
    Goraca A, Piechota A, Huk-kolega H (2009) Effect of alpha—lipoic acid on LPS-induced oxidative stress in the heart. J Physiol Pharmacol 60(1):61–68PubMedGoogle Scholar
  26. 26.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  27. 27.
    Petit T (2004) Anthracycline-induced cardiotoxicity. Bull Cancer 91(3):159–165PubMedGoogle Scholar
  28. 28.
    Zhang FY, Du GJ, Zhang L, Zhang CL, Lu WL, Liang W (2009) Naringenin enhances the anti-tumor effect of Doxorubicin through selectively inhibiting the activity of multidrug resistance associated proteins but not P-glycoprotein. Pharm Res 26:914–925PubMedCrossRefGoogle Scholar
  29. 29.
    Xiao J, Sun GB, Sun B et al (2012) Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. Toxicology 292:53–62PubMedCrossRefGoogle Scholar
  30. 30.
    Deatley SM, Aksenov MY, Aksenova MV, Jordan B, Carney JM, Butterfield DA (1999) Adriamycin-induced changes of creatine kinase activity in vivo and in cardiomyocyte culture. Toxicology 134:51–62PubMedCrossRefGoogle Scholar
  31. 31.
    Mair J, Apple F (1997) Progress in myocardial damage detection: new biochemical markers for clinicians. Crit Rev Clin Lab Sci 34:1–66PubMedCrossRefGoogle Scholar
  32. 32.
    Herman EH, Zhang J, Rifai N et al (2001) The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin-and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48:297–304PubMedCrossRefGoogle Scholar
  33. 33.
    Saad SY, Najjar TA, Al-Rikabi AC (2001) The preventive role of desferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res 43:211–218PubMedCrossRefGoogle Scholar
  34. 34.
    El-Demerdash E, Ali AA, Ahmed MS, Osman AM (2003) New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol 52:411–416PubMedCrossRefGoogle Scholar
  35. 35.
    Sakr SA, Mahran HA, Lamfon HA (2011) Protective effect of ginger (Zingiber officinale) on adriamycin-induced hepatotoxicity in albino rats. J Med Plant Res 5(1):133–140Google Scholar
  36. 36.
    Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM (1997) Activation of the receptor for advanced glycation end products triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272:17810–17814PubMedCrossRefGoogle Scholar
  37. 37.
    Li N, Karin M (1999) Is NF-kappa B the sensor of oxidative stress? FASEB J 13:1137–1143PubMedGoogle Scholar
  38. 38.
    Wang S, Kotamraju S, Konorev E, Kalivendi S, Joseph J, Kalyanaraman B (2002) Activation of NF-κB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochemical J 367:729–740CrossRefGoogle Scholar
  39. 39.
    Liu J, Mao W, Ding B, Liang CS (2008) ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol 295:1956–1965CrossRefGoogle Scholar
  40. 40.
    Tam XH, Shiu SW, Leng L, Bucala R, Betteridge DJ, Tan KC (2011) Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in type 2 diabetes. Clin Sci 120:81–89PubMedCrossRefGoogle Scholar
  41. 41.
    Pereira MM, Haniadka R, Chacko PP, Palatty PL, Baliga MS (2011) Zingiber officinale Roscoe (ginger) as an adjuvant in cancer treatment: a review. J BUON 16(3):414–424PubMedGoogle Scholar
  42. 42.
    Ryan JL, Heckler C, Dakhil SR et al (2009) Ginger for chemotherapy-related nausea in cancer patients: a URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients. J Clin Oncol 27:15sCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Wesam M. El-Bakly
    • 1
  • Manal L. Louka
    • 2
  • Ali M. El-Halawany
    • 3
  • Mona F. Schaalan
    • 4
  1. 1.Department of Pharmacology and Therapeutics, Faculty of MedicineAin Shams UniversityCairoEgypt
  2. 2.Department of Medical Biochemistry and Molecular Biology, Faculty of MedicineAin Shams UniversityCairoEgypt
  3. 3.Department of Pharmacognosy, Faculty of Pharmacy, Kasr El AinyCairo UniversityCairoEgypt
  4. 4.Department of Biochemistry, Faculty of PharmacyMisr International UniversityCairoEgypt

Personalised recommendations