Skip to main content
SpringerLink
Log in

Prevention of doxorubicin-induced cardiotoxicity by melatonin

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents. Cardiotoxicity made by these agents develops as a complication of the cancer chemotherapy. Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. We decided to evaluate the tissue-protective effect of melatonin against myocardial toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose) and melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD). The degree of cardiac muscle cell alterations were examined either histologically (mean total score technique) or biochemically. In doxorubicin-treated group, malondialdehyde (MDA) levels of the heart tissue were significantly increased, glutathione (GSH) levels were decreased compared to the control rats. In the group in which first doxorubicin and then melatonin was given, MDA levels were significantly decreased and glutathione (GSH) levels were increased compared to the doxorubicin-treated group. During ultrastructural analysis, in doxorubicin-treated group, cellular edema, mitochondrial deformation, decreased glycogen stores, and disordered myofibrillary structure were observed. In contrast, in first doxorubicin and then melatonin-treated group, normal cellular structure was observed. But, first melatonin and then doxorubicin-treated group was not significantly preserved from the doxorubicin-induced changes. By preventing lipid peroxidation and myocardial lesions, melatonin may be highly effective in protecting against doxorubicin-induced cardiotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Olson RD, Mushlin PS: Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4: 3076–3086, 1990

    PubMed  CAS  Google Scholar 

  2. Rajagopalan S, Politi PM, Sinha BK, Myers E: Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res 48 (17): 4766–4769, 1988

    PubMed  CAS  Google Scholar 

  3. Lee V, Randhawa AK, Singal PK: Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals. Am J Physiol 261: H989–995, 1991

    PubMed  CAS  Google Scholar 

  4. Sarvazyan NA, Askari A, Huang WH: Effects of doxorubicin on cardiomyocytes with reduced level of superoxide dismutase. Life Sci 57: 1003–1010, 1995

    Article  PubMed  CAS  Google Scholar 

  5. Singal PK, Siveski-Iliskovic N, Hill M, Thomas TP, Li T: Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. J Mol Cell Cardiol 27: 1055–1063, 1995

    Article  PubMed  CAS  Google Scholar 

  6. Vora J, Khaw B A, Narula J, Boroujerdi M: Protective effect of butylated hydroxyanisole on adriamycin induced cardiotoxicty. J Pharm Pharmacol 48: 940–944, 1996

    PubMed  CAS  Google Scholar 

  7. Reiter R, Tang L, Garcia JJ, Munoz-Hoyos A: Pharmalogical actions of melatonin in oxygen radical pathophysiology. Life Sci 60: 2255–2271, 1997

    Article  PubMed  CAS  Google Scholar 

  8. Neri B, de Leonardis V, Gemelli MT, di Loro F, Mottola A, Ponchietti R, Raugei A, Cini G: Melatonin as biological response modifier in cancer patients. Anticancer Res 18: 1329–1332, 1998

    PubMed  CAS  Google Scholar 

  9. Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC: Melatonin, hydroxy radical-mediated oxidative damage, and aging: A hypothesis. J Pineal Res 14: 151–168, 1993

    Article  PubMed  CAS  Google Scholar 

  10. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F: Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci 55:PL 271–276, 1994

    Article  CAS  Google Scholar 

  11. Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabo C: Melatonin is a scavenger of peroxynitrite. Life Sci 60: PL 169–174, 1997

    Article  CAS  Google Scholar 

  12. Li ZR, Reiter RJ, Fujimori O, Oh CS, Duan YP: Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: Preventive actions of melatonin. J Pineal Res 22 : 117–123, 1997

    Article  PubMed  CAS  Google Scholar 

  13. Bertuglia S, Marchiafava PL, Colantuoni A: Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. Cardiovasc Res 31: 947–952, 1996

    Article  PubMed  CAS  Google Scholar 

  14. Duncker DJ, Verdouw PD: Has melatonin a future as a cardioprotective agent? Cardiovasc Drugs Ther 15: 205–207, 2001

    Article  PubMed  CAS  Google Scholar 

  15. Sahna E, Parlakpı nar H, Özer MK, Öztürk F, Özuğurlu F, Acet A: Melatonin protects against myocardial doxorubicin toxicity in rats: Role of physiological concentrations. J Pineal Res 35: 257–261, 2003

    Article  PubMed  CAS  Google Scholar 

  16. Ahmed HH, Mannaa F, Elmegeed GA, Doss SH: Cardioprotective activity of melatonin and its novel synthesized derivates on doxorubicin-induced cardiotoxicity. Bioorg Med Chem 13: 1847–1857, 2005

    Article  PubMed  CAS  Google Scholar 

  17. Timlioğlu Ö, Kutsal Ş, Özkur M, Uluoğlu Ö, Arı cı oğlu A, Çevik C, Düzgün E, Sancak B, Poyraz A: The effect of EGb 761 on the doxorubicin cardiomyopathy. Res Commun Mol Pathol Pharmacol 106: 181–192, 1999

    Google Scholar 

  18. Akbulut KG, Gönül B, Akbulut H: Differential effects of pharmacological doses of melatonin on malondialdehyde and glutathione levels in young and old rats. Gerontology. 45: 67–71, 1999

    Article  PubMed  CAS  Google Scholar 

  19. Kurtel H, Granger D N, Tso P, Grisham MB: Vulnerability of intestinal interstitial fluid the oxidant stres. Am J Physiol 263: G573–578, 1992

    PubMed  CAS  Google Scholar 

  20. Casini A, Ferrali M, Pompella A, Maellaro E, Comborti M: Lipid reroxidation and cellular damage in extrahepatic tissues of bromobenzene intoxicated mice. Am J Pathol 123: 520–531, 1986

    PubMed  CAS  Google Scholar 

  21. Kozluca O, Olcay E, Sürücü S, Güran Z, Kulaksı z T, Üskent N: Prevention of doxorubicin induced cardiotoxicity by catechin. Cancer Lett 98: 1–6, 1995

    Google Scholar 

  22. Liu X, Chen Z, Chua CC, Ma YS, Youngberg GA, Hamdy R, Chua BH: Melatonin as an effective protector against doxorubicin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 283: H254–263, 2002

    PubMed  CAS  Google Scholar 

  23. Agapito MT, Antolin Y, del Brio MT, Lopez-Burillo S, Pablos MI, Recio JM: Protective effect of melatonin against adriamycin toxicity in the rat. J Pineal Res 31: 23–30, 2001

    Article  PubMed  CAS  Google Scholar 

  24. Xu MF, Tang PL, Qian ZM, Ashraf M: Effects by doxorubicin on the myocardium are mediated by oxygen free radicals. Life Sci 68: 889–901, 2001

    Article  PubMed  CAS  Google Scholar 

  25. Doroshow JH, Locker GY, Myers CE: Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 65: 128–135, 1980

    Article  PubMed  CAS  Google Scholar 

  26. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F: Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 55: PL 271–276, 1994

    Article  CAS  Google Scholar 

  27. Hardeland R, Reiter RJ, Poeggeler B, Tan DX: The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev 17: 347–357, 1993

    Article  PubMed  CAS  Google Scholar 

  28. Meister A: Glutathione deficiency produced by inhibition of it's synthesis and it's reversal : applications in research and therapy. Pharmacol Ther 51: 155–194, 1991

    Article  PubMed  CAS  Google Scholar 

  29. Dziegiel P, Murawska-Cialowicz E, Jethon Z, Januszewska L, Podhorska-Okolow M, Surowiak P, Zawadzki M, Rabczynski J, Zabel M: Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication. J Pineal Res 35: 183–187, 2003

    Article  PubMed  CAS  Google Scholar 

  30. Wallace KB: Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 93: 105–115, 2003

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Gazi University, Uğurlu sokak 38/4 Kurtuluş, Ankara, 06600, Turkey

    Eser Öz & Deniz Erbaş

  2. Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    H. Selçuk Sürücü

  3. Department of Biochemistry, Bayindir Hospital Kavaklı dere, Ankara, Turkey

    Ersel Düzgün

Authors
  1. Eser Öz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deniz Erbaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Selçuk Sürücü
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ersel Düzgün
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eser Öz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Öz, E., Erbaş, D., Sürücü, H.S. et al. Prevention of doxorubicin-induced cardiotoxicity by melatonin. Mol Cell Biochem 282, 31–37 (2006). https://doi.org/10.1007/s11010-006-1153-9

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-1153-9

Key words

Search

Navigation