Cardioprotective Effects of Fullerenol C 60 (Oh) 24 on a Single Dose Doxorubicin-induced Cardiotoxicity in Rats with Malignant Neoplasm

Abstract

The therapeutic utility of the anthracycline antibiotic doxorubicin is limited due to its cardiotoxicity. Our aim was to investigate the efficacy of fullerenol C₆₀(OH)₂₄ in preventing single, high-dose doxorubicin-induced cardiotoxicity in rats with malignant neoplasm. Experiment was performed on adult female Sprague Dawley rats with chemically induced mammary carcinomas. The animals were sacrificed two days after the application of doxorubicin and/or fullerenol, and the serum activities of CK, LDH and α-HBDH, as well as the levels of MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS in the heart, were determined. The results obtained from the enzymatic activity in the serum show that the administration of a single dose of 8 mg/kg in all treated groups induces statistically significant damage. There are significant changes in the enzymes of LDH and CK (p < 0.05), after an i.p. administration of doxorubicin/fullerenol and fullerenol. Comparing all groups with untreated control group, point to the conclusion that in the case of a lower α-HBDH/LDH ratio, results in more serious the liver parenchymal damage. The results revealed that doxorubicin induced oxidative damage and that the fullerenol antioxidative influence caused significant changes in MDA, GSH, GSSG, GSH-Px, SOD, CAT, GR, and TAS level in the heart (p < 0.05). Therefore, it is suggested that fullerenol might be a potential cardioprotector in doxorubicin-treated individuals.

Keywords

Cardioprotection Doxorubicin Fullerenol Oxidative stress Heart Rats Mammary carcinomas

References

Weiss

R. B.

The anthracyclines: Will we ever find a better doxorubicin?

Semin Oncol 19, 670–686 (1992).

Lefrak

E. A.

Pitha

Rosenheim

A clinicopathologic analysis of adriamycin cardioxicity. Cancer 32, 302–314 (1973).

Singal

P. K.

Iliskovic

Doxorubicin-induced cardiomyopathy. N Engl J Med 339, 900–905 (1998).

Menna

Minotti

Salvatorelli

In vitro modeling of the structure-activity determinants of anthracycline cardiotoxicity. Cell Biol Toxil 23, 49–62 (2007).

Takemura

Fujiwara

Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog cardiovasc Dis 49, 330–352 (2007).

Davis

K. J.

Doroshow

J. H.

Redox cycling of anthracyclines by cardiac mitochondria. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem 261, 3060–3067 (1986).

Siveski-Iliskovic

Hill

Chow

D. A.

Probucol protects against adriamycin cardiomyopathy without interfering with its anti-tumor effect. Circulation 91, 10–15 (1995).

Doroshow

J. H.

Locker

G. Y.

Myers

C. E.

Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. J Clin Invest 65, 128–135 (1980).

Danelisen

Singal

P. K.

Early changes in myocardial antioxidant enzymes in rats treated with adryamycin. Mol Cell Biochem 232, 19–26 (2002).

10.

Doroshow

J. H.

Locker

G. Y.

Baldinger

The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 26, 285–295 (1979).

11.

Myers

Bonow

Palmeri

A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 10, 53–55 (1983).

12.

Singal

P. K.

Pierce

G. N.

Adriamycin stimulates low-affinity Ca+2 binding and lipid peroxidation but depresses myocardial function. Am J Physiol 250, H419–H425 (1986).

13.

Jeyaseelan

Poizat

Baker

R. K.

A novel cardiac-restricted target for doxorubicin CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem 272, 22800–8 (1997).

14.

Minotti

Menna

Salvatorelli

Cairo

Gianni

Anthracyclines: Molecular advances and pharmacologic developments in anti-tumor activity and cardiotoxicity. Pharmacol Rev 56, 185–229 (2004).

15.

Zhou

Starkov

Froberg

M. K.

Leino

R. L.

Wallace

K. B.

Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61, 771–777 (2001).

16.

Singal

P. K.

Iliskovic

Kumar

Adriamycin cardiomyopathy: Pathophysiology and prevention. FASEB J 11, 931–936 (1997).

17.

Singal

P. K.

Kumar

Danelisen

Iliskovic

Adriamycin-induced heart failure: Mechanism and modulation. Mol Cell Biochem 207, 77–85 (2000).

18.

Ahmed

H. H.

Mannaa

Elmegeed

G. A.

Doss

S. H.

Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity. Bioorg Med Chem 13, 1847–1857 (2005).

19.

Mukherjee

Banerjee

S. K.

Maulik

Dinda

A. K.

Talwar

K. K.

Maulik

S. K.

Protection against acute adriamycin-induced cardiotoxicity by garlic: Role of endogenous antioxidants and inhibition of TNF-α expression. BMC Pharmacol 3, 16–24 (2003).

20.

Gnanapragasam

Yogeeta

Subhashini

Ebenezar

K. K.

Sathish

Devaki

Adriamycin induced myocardial failure in rats: Protective role of Centella asiatica. Mol Cell Biochem 294, 55–63 (2007).

21.

Minotti

Cairo

Monti

Role of iron in anthracycline cardiotoxicity: New tunes for an old song?

FASEB J 13, 199–212 (1993).

22.

Zucchi

Danesi

Cardiac toxicity of antineoplastic anthracyclines. Curr Med Chem 3, 151–71 (2003).

23.

Ladas

E. J.

Jacobson

J. S.

Kennedy

D. D.

Antioxidants and cancer therapy: A systematic review. J Clin Oncol 22, 517–28 (2004).

24.

Bogdanovic

Kojic

Djordjevic

Canadanovic-Brunet

Vojinovic-Miloradov

Baltic

Modulating activity of fullerenol C60(OH)22 on doxorubicin induced cytotoxicity. Toxicology in vitro 18, 629–637 (2004).

25.

Mirkov

Djordjevic

Andric

Kostic

Bogdanovic

Vojinovic-Miloradov

Kovacevic

Nitric oxide-scavenging activity of polyhydroxylated fullerenol. Nitric Oxide 11, 201–207 (2004).

26.

Trajkovic

Dobric

Djordjevic

Dragojevic-Simic

Milovanovic

Radioprotective efficiency of fullerenol in irradiated mice. Mater Sci Forum 494, 549–554 (2005).

27.

Djordjevic

Canadanovic-Brunet

Vojinovic-Miloradov

Bogdanovic

Antioxidant properties and hypothetical radical mechanism of fullerenol C₆₀(OH)₂₄. Oxidation Communications 27, 806–812 (2005).

28.

Djordjevic

Bogdanovic

Dobric

Fullerenes in biomedicine. J BUON 11, 391–404 (2006).

29.

Djordjevic-Milic

Djordjevic

Dobric

, Injac, R., Vuckovic, D., Stankov, K., Dragojevic-Simic, V., and Suvajdzic, Lj. Influence of fullerenol C60(OH)24 on doxorubicin induced cardiotoxicity in rats. Mater Sci Forum 518, 525–529 (2006).

30.

Trajkovic

Dobric

Jacevic

Dragojevic-Simic

Milovanovic

Djordjevic

Tissue-protective effects of fullerenol C₆₀(OH)₂₄ and amifostine. Colloids and Suferfaces B: Biointerfaces 58, 39–43 (2007).

31.

Djordjevic

Vojinovic-Miloradov

Petranovic

Devecerski

Lazar

Ribar

Catalytic preparation and characterization of C₆₀Br₂₄. Fullerene Sci Technol 6, 689–94 (1998).

32.

Liska

Galbavy

Macejova

Zlatos

Brtko

Histopathology of mammary tumors in female rats treated with 1-methyl-1-nitrosourea. Endocr Regul 34, 91–96 (2000).

33.

Aebi

Catalase

in vitro. Methods Enzymol 105, 121–126 (1984).

34.

Speyer

J. L.

Green

M. D.

Kramer

Protecive effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardia toxicity in women with advanced breast cancer. N Engl J Med 319, 745–752 (1988).

35.

Curran

C. F.

Narang

P. K.

Reynolds

R. D.

Toxicity profile of dexrazoxane (Zinecard, ICRF-187, ADR-529, NSC-169780), a modulator of doxorubicin cardiotoxicity. Cancer Treat Rev 18, 241–252 (1991).

36.

Seifert

C. F.

Nesser

M. E.

Thompson

D. F.

Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 28, 1063–1072 (1994).

37.

Tetef

M. L.

Synold

T. W.

Chow

Phase I trial of 96-hour continuous infusion of dexrazone in patients with advanced malignancies. Clin Cancer Res 7, 1569–1576 (2001).

38.

Sacco

Bigioni

Evangelista

Goso

Cardioprotective effects of zofenopril, a new angiotension-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat. Eur J Pharmacol 414, 71–8 (2001).

39.

Van Acker

F. A. A.

Hulshof

J. W.

Haenen

G. R. M. M.

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. Free Radic Biol Med 31, 31–37 (2001).

40.

Khan

Varadharaj

Shobha

J. C.

Naidu

M. U.

Cphycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes. J Cardiovasc Pharmacol 47, 9–20 (2006).

41.

Bjelogrlic

S. K.

Radic

Jovic

Radulovic

Activity of d,l-alpha-tocopherol (vitamin E) against cardiotoxicity induced by doxorubicin and doxorubicin with cyclophosphamide in mice. Basic Clin Pharmacol Toxicol 97, 311–319 (2005).

42.

Mizushima

Sassa

Hamayaki

Fujishita

Oosaki

Kobayashi

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumor. Brit J Cancer 78, 1030–1034 (1998).

43.

Bellhorn

R. W.

Korte

G. E.

Abrutyn

Spontaneous corneal degeneration in the rat. Lab Anim Sci 38, 46–50 (1988).

44.

Hoffman

Benz

E. J.

Jr. Shattil

S. J.

, eds. In: Hematology: Basic Principles and Practice . 4th ed. Philadelphia, Pa: Churchill Livingston, p. 2674 (2005).

45.

Kwok

J. C.

Richardson

D. R.

Examination of the mechanism involved in doxorubicin-mediated iron accumulation in ferritin: Studies using metabolic inhibitors, protein synthesis inhibitors and lysosomotropic agents. Mol Pharmacol 65, 181–95 (2004).

46.

Oliveira

P. J.

Bjork

A. J.

Santos

S. M.

Leino

R. L.

Froberg

M. Kent

Moreno

A. J.

Wallace

K.B.

Carvidilol mediated antioxdant protection against doxorubicin induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 200, 159–168 (2004).

47.

Balanehru

Nagarajan

Intervention of adriamycin induced free radical damage. Biochem Int 28, 735–744 (1992).

48.

Stadtman

E. R.

Protein oxidation and aging. Science 257, 1220–1224 (1992).

49.

Mimnaugh

E. G.

Trush

M. A.

Mohit

Bhatnagar Gram F. E.

Enhancement of reactive oxygen dependant mitochondrial membrane lipid peroxidation by the anti cancer drug adriamyin. Biochem Pharmacol 34, 847–856 (1985).

50.

Halliwell

Gutteridge

J. M. C.

, eds. In: Free radicals in biology and medicine . 3rd edition. Oxford science press Inc. New York, pp 126 and 717 (2005).

51.

Mills

B. J.

Richie

J. P.

Lang

C. A.

Jr.

Glutathione disulfide variability in normal human blood. Anal Biochem 222, 95–101 (1994).

52.

Blum

Fridovich

Inactivation of glutathione peroxidase by superoxide radical. Arch Biochem Biophys 249, 500–508 (1985).

53.

Scheulen

M. E.

Hoensch

Kappus

Positive correlation between decreased cellular uptake, NADPH-glutathione reductase activity and adriamycin resistance in Ehrlich ascites tumor lines. Arch Toxicol 60, 154–7 (1987).

54.

Lindeman

J. H. N.

Van Zoeren-Grobbenm

Schrijver

The total free radical trapping ability of cord blood plasma in preterm and term babies. Pediatr Res 26, 20–24 (1989).

55.

Miller

N. J.

Rice-Evans

Davies

M. J.

A new method for measuring antioxidant activity. Biochem Soc Trans 21, 95S (1993).