Molecular and Cellular Biochemistry

, Volume 286, Issue 1–2, pp 11–15 | Cite as

Effects of melatonin in reducing the toxic effects of doxorubicin

  • Eser Öz
  • Mustafa N. İlhan


Anthracycline antibiotics, such as doxorubicin and daunorubicin, constitute a group of wide spectrum therapeutic agents. Application of these drugs in chemotherapy is limited because of their toxic effects. Melatonin, the main secretory product of pineal gland, was recently found as a free radical scavenger and antioxidant.

We decided to evaluate the tissue protective effect of melatonin against toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose), melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD).

The degree of kidney, lung, liver and brain cells' alterations were examined biochemically.

In doxorubicin-treated group, malondialdehyde (MDA) levels of kidney, lung, liver and brain tissues were significantly increased but glutathione (GSH) levels were decreased compared to control rats. In the group in which first doxorubicin and then melatonin were given, MDA levels were significantly decreased compared to the doxorubicin-treated group.

In doxorubicin-treated group, serum levels of creatinine, uric acid, blood urea nitrogen (BUN), Gamma-glutamyl transpeptidase (GGT) and Lactic acid dehydrogenase (LDH) were significantly increased while serum albumin and total protein levels were significantly decreased compared to control rats.

Melatonin decreased the intensity of the changes produced by the administration of doxorubicin alone. Melatonin was quite efficient in reducing the formation of lipid peroxidation, restoring the tissue GSH contents and alterations of serum levels.


doxorubicin-induced toxicity lipid peroxidation melatonin 


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  1. 1.
    Agapito MT, Antolin Y, del Brio MT, Lopes-Burillo S, Pablos MI, Recio JM: Protective effect of melatonin against adriamycin toxicity in the rat. J Pineal Res 31: 23–30, 2001PubMedCrossRefGoogle Scholar
  2. 2.
    Olson RD, Mushlin PS: Doxorubicin cardiotoxicity: analysis of prevailing hypotheses.The FASEB Journal 4: 3076–3086, 1990PubMedGoogle Scholar
  3. 3.
    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, 1988PubMedGoogle Scholar
  4. 4.
    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, 1995PubMedCrossRefGoogle Scholar
  5. 5.
    Reiter R, Tang L, Garcia JJ, Munoz-Hoyos A: Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci 60: 2255–2271, 1997PubMedCrossRefGoogle Scholar
  6. 6.
    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, 1998PubMedGoogle Scholar
  7. 7.
    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, 1993PubMedCrossRefGoogle Scholar
  8. 8.
    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, 1994CrossRefGoogle Scholar
  9. 9.
    Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabo C: Melatonin is a scavenger of peroxynitrite. Life Sci 60: PL 169–174, 1997CrossRefGoogle Scholar
  10. 10.
    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, 1997PubMedCrossRefGoogle Scholar
  11. 11.
    Bertuglia S, Marchiafava PL, Colantuoni A: Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. Cardiovasc Res 31: 947–952, 1996PubMedCrossRefGoogle Scholar
  12. 12.
    Duncker DJ, Verdouw PD: Has melatonin a future as a cardioprotective agent? Cardiovasc. Drugs and Therapy 15: 205–207, 2001CrossRefGoogle Scholar
  13. 13.
    Montilla PL, Tunez IF, Munoz de Agueda C, Gascon FL, Soria JV: Protective role of melatonin and retinol palmitate in oxidative stress and hyperlipidemic nephropathy induced by adriamycin in rats. J Pineal Res 25(2): 86–93, 1998PubMedCrossRefGoogle Scholar
  14. 14.
    Montilla P, Tunez I, Munoz MC, Lopez A, Soria JV: Hyperlipidemic nephropathy induced by adriamycin: effect of melatonin administration. Nephron 76(3): 345–350, 1997PubMedCrossRefGoogle Scholar
  15. 15.
    Rapozzi V, Comelli M, Mavelli I, Sentjurc M, Schara M, Perissin L, Giraldi T: Melatonin and oxidative damage in mice liver induced by the prooxidant antitumor drug, adriamycin. In vivo 13(1): 45–50, 1999PubMedGoogle Scholar
  16. 16.
    Baydas G, Ercel E, Canatan H, Dönder E, Akyol A: Effect of melatonin on oxidative status of rat brain, liver and kidney tissues under constant light exposure. Cell Biochem Funct 19: 37–41, 2001PubMedCrossRefGoogle Scholar
  17. 17.
    Timlioğlu Ö, Kutsal Ş, Özkur M, Uluoğlu Ö, Arıcıoğlu A, Çevik C, Düzgün E, Sancak B, Poyraz A: The effect of EGb 761 on the doxorubicin cardiomyopathy. Research Communications in Molecular Pathology and Pharmacology 106: 181–192, 1999Google Scholar
  18. 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, 1999PubMedCrossRefGoogle Scholar
  19. 19.
    Kurtel H, Granger DN, Tso P, Grisham MB: Vulnerability of intestinal interstitial fluid to oxidant stres. Am J Physiol 263: G573–578, 1992PubMedGoogle Scholar
  20. 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, 1986PubMedGoogle Scholar
  21. 21.
    Oz E, Erbas D, Sürücü HS, Düzgün E: Prevention of doxorubicin induced cardiotoxicity by melatonin. Molecular and Cellular Biochemistry, in pressGoogle Scholar
  22. 22.
    Booser DJ, Hortobagyi GN: Anthracycline antibiotics in cancer therapy. Drugs 47: 223–258, 1994PubMedCrossRefGoogle Scholar
  23. 23.
    Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25: 72–85, 1998PubMedGoogle Scholar
  24. 24.
    Hortobagyi GN: Anthracyclines in the treatment of cancer. Drugs 54: 1–7, 1997PubMedCrossRefGoogle Scholar
  25. 25.
    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, 1994CrossRefGoogle Scholar
  26. 26.
    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, 1993PubMedCrossRefGoogle Scholar
  27. 27.
    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, 1991PubMedCrossRefGoogle Scholar
  28. 28.
    Tunez I, del Carmen Munoz M, Feijoo M, Valdervira ME, Rafael Munoz-Castaneda J, Montilla P: Melatonin effect on renal oxidative stress under constant light exposure. Cell Biochem Funct 21(1): 35–40, 2003PubMedCrossRefGoogle Scholar
  29. 29.
    Tunez L, Munoz MC, Feijoo-Lopez AL, Valdvira E, Bujalance-Arenas L, Montilla P: Effect of melatonin on hyperlipidemic nephropathy under constant light exposure. J Physiol Biochem 58(2): 109–114, 2002PubMedCrossRefGoogle Scholar
  30. 30.
    Montilla P, Tunez I, Munoz MC, Soria JV, Lopez A: Antioxidative effect of melatonin in rat brain oxidative stress induced by adriamycin. Rev Esp Fisiol 53(3): 301–305, 1997PubMedGoogle Scholar
  31. 31.
    Rapozzi V, Zorzet S, Comelli M, Mavelli I, Perissin L, Giraldi T: Melatonin} decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma. Life Sciences 63(19): 1701–1713, 1998PubMedCrossRefGoogle Scholar
  32. 32.
    Granzotti M, Rapozzi V, Decorti G, Giraldi T: Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells. J Pineal Res 31: 206–213, 2001CrossRefGoogle Scholar
  33. 33.
    Dziegiel P, Suder E, Surowiak P, Jethon Z, Rabczynski J, Januszewska L, Sopel M, Zabel M: Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat. J Pineal Res 33: 95–100, 2002PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of PhysiologyFaculty of Medicine, Gazi UniversityAnkaraTurkey
  2. 2.Department of Public HealthFaculty of Medicine, Gazi UniversityAnkaraTurkey
  3. 3.Uğurlu sokakAnkaraTurkey

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