Abstract
Cancer therapy with the anthracycline doxorubicin (Dox) is limited by cardiomyopathy, which develops in animals and patients after cumulative dosing. Generation of free radicals by Dox may be involved in this cardiotoxicity. Dox binds strongly to metal ions, especially iron(III). This Dox-metal complex stimulates the generation of free radicals through self-reduction of the complex. We investigated the possibility of inhibiting Dox-induced cardiotoxicity by scavenging of free radicals and/or chelating metal ions. The effects of Dox, both alone and in combination with iron-chelating agents, were studied on inotropy of the isolated mouse left atrium, lipid peroxidation (LPO) in cardiac microsomal membranes, ferricytochrome c (cyt.c3+) reduction, and oxygen consumption. The flavonoids 7-monohydroxyethylrutoside (mono-HER) and 7,3′,4′-trihydroxyethylrutoside (tri-HER) and the ethylenediaminetetraacetic acid (EDTA) analogue ICRF-198 and its precursor ICRF-187 were used as iron-chelating agents. The latter were used for comparison since ICRF-187 has been reported to inhibit the cardiotoxic effects of Dox both in vitro and in vivo. Only the flavonoids could inhibit the negative inotropic effect of Dox (35μM) on the mouse left atrium; in the presence of tri-HER (500 μM) the beating force decreased by 18% instead of 50%, whereas mono-HER completely prevented the Dox-induced negative inotropic effect. ICRF-198 and both flavonoids (500 μM) completely inhibited Dox (35μM)-induced LPO, whereas ICRF-187 provided 65% inhibition. The observation that both cyt.c3+ reduction and oxygen consumption induced by the Dox-iron(III) complex (50/16.6 μM Dox3Fr3+) could be inhibited by superoxide dismutase proved the involvement of superoxide anions (O ⊙−2 ). The iron-chelating agents (50 μM) inhibited cyt.c3+ reduction by 91% (mono-HER), 43% (tri-HER), and 100% (ICRF-198). Only mono-HER and ICRF-198 (50 μM) were capable of inhibiting the oxygen consumption by 70% and 43%, respectively. It is concluded that flavonoids offer a good perspective for further studies on the prevention of Dox-induced cardiomyopathy.
Similar content being viewed by others
References
Bachur NR, Gordan SL, Gee MV (1977) Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 13: 901
Bast A, Haenen GRMM (1990) Antioxidant capacity of constituents of Venoruton. Int J Microcirc Clin Exp 9: 177
Beraldo H, Garnier-Suillerot A, Tosi L, Lavelle F (1985) Iron(III)-Adriamycin and iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA and antitumor activity. Biochemistry 24: 284
Chappell JB (1964) The oxidation of citrate, isocitrate and cis-aconitate by isolated mitochondria. Biochem J 90: 225
De Jong J, Schoofs PR, Onderwater RCA, Van der Vijgh WJF, Pinedo HM, Bast A (1990) Isolated mouse atrium as a model to study anthracycline cardiotoxicity: the role of the β-adrenoceptor system and reactive oxygen species. Res Commun Chem Pathol Pharmacol 68: 275
De Jong J, Schoofs PR, Snabilié AM, Bast A, Van der Vijgh WJF (1993) The role of biotransformation in anthracyline-induced cardiotoxicity in mice. J Pharmacol Exp Ther 266: 312
Demant EJF (1984) Transfer of ferritin-bound iron to adriamycin. FEBS Lett 176: 97
Dodd NJF, Mukherjee T (1984) Free radical formation from anthracycline antitumour agents and model systems. I. Model naphtoquinones and anthraquinones. Biochem Pharmacol 33: 379
Doroshow JH (1983) Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43: 460
Doroshow JH, Locker GY, Myers CE (1979) Experimental animal models of Adriamycin cardiotoxicity. Cancer Treat Rep 63: 855
Gianni L, Zweier JL, Levy A, Myers CE (1985) Characterization of the cycle of iron-mediated electron transfer from Adriamycin to molecular oxygen. J Biol Chem 260: 6820
Gianni L, Vigano L, Lanza C, Niggeler M, Malatesta V (1988) Role of daunosamine and hydroxyl side chain in reaction with iron and lipid peroxidation by anthracyclines. J Natl Cancer Inst 80: 1104
Green MD, Alderton P, Gross J, Muggia FM, Speyer JL (1990) Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187. Pharmacol Ther 48: 61
Gutteridge JMC (1984) Lipid peroxidation and possible hydroxyl radical formation stimulated by the self-reduction of a doxorubicin-iron(III) complex. Biochem Pharmacol 33: 1725
Haenen GRMM, Bast A (1983) Protection against microsomal lipid peroxidation by a glutathione dependent heat labile factor. FEBS Lett 159: 24
Hasinoff BB (1989) The interaction of the cardioprotective agent ICRF-187 [(+)-1,2,-bis(3,5-dioxopiperazin-1-yl) propane]; its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents Actions 26: 378
Hasinoff BB (1989) Self-reduction of the iron(III)-doxorubicin complex. Free Radical Biol Med 7: 583
Hasinoff BB (1990) The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187. Agents Actions 29: 374
Hasinoff BB, Davey JP, O'Brien PJ (1989) The Adriamycin (doxorubicin) induced inactivation of cytochrome c oxidase depends on the presence of iron or copper. Xenobiotica 19: 231
Havsteen B (1983) Flavonoids, a class of natural products of high pahrmacological potency. Biochem Pharmacol 32: 1141
Herman EH, Ferrans VJ, Young RSK, Hamlin RL (1988) Effect of pretreatment with ICRF-187 on the total cumulative dose of doxorubicin tolerated by beagle dogs. Cancer Res 48: 6918
Hermansen K, Rasmussen IMN, Schou HS (1990) The isolated mouse atria as a new model for testing cardioactive drugs with special reference to doxorubicin (Adriamycin). Pharmacol Toxicol 66: 299
Huang Z-X, May PM, Quinlan KM, Williams DR, Creighton AM (1982) Metal binding by pharmaceuticals. 2. Interactions of Ca(II), Cu(II), Fe(II), Mg(II), Mn(II) and Zn(II) with the intracellular hydrolysis products of the antitumor agent ICRF-159 and its inactive homologue ICRF-192. Agents Actions 12: 536
Minotti G (1990) NADPH- and Adriamycin-dependent microsomal release of iron and lipid peroxidation. Arch Biochem Biophys 277: 268
Myers CE, Gianni L, Simone SB, Klecker R, Greene R (1982) Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry 21: 1707
Powis G (1987) Metabolism and reactions of quinoid anti-cancer agents. Pharmacol Ther 35: 57
Ryan TP, Samokyszyn VM, Dellis S, Aust SD (1990) Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl) propane (ADR-529) on iron catalyzed lipid peroxidation. Chem Res Toxicol 3: 384
Sobol MM, Amiet RG, Green MD (1992) In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane] onto an existing ferric-anthracycline complex. Mol Pharmacol 41: 8
Someya A and Tanaka N (1979) DNA strand scission induced by adriamycin and a clacinomycin A. Antibiotics 32: 839
Speyer JL, Green MD, Kramer E, Rey M, Sanger J, Ward C, Dubin N, Ferrans V, Stecy P, Jacquotte-Zeleniuch A, Wernz J, Feit F, Slater W, Blum R, Muggia F (1988) Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 319: 745
Thompson M, Williams CR (1976) Stability of flavonoid complexes of copper(II) and flavonoid antioxidant activity. Anal Chem Acta 85: 375
Van Acker SABE, Voest EE, Beems DB, Madhuizen HT, De Jong J, Bast A, Van der Vijgh WJF (1993) Cardioprotective properties ofO-(β-hydroxyethyl)-rutosides in doxorubicin-pretreated BALB/c mice. Cancer Res 53: 4603
Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710
Wallace KB (1986) Nonenzymatic oxygen activation and stimulation of lipid peroxidation by doxorubicin-copper. Toxicol Appl Pharmacol 86: 69
Winterbourn CC (1981) Cytochrome c reduction by semiquinone radicals can be directly inhibited by superoxide dismutase. Arch Biochem Biophys 290: 159
Winterbourn CC (1982) Superoxide-dismutase-inhibitable reduction of cytochrome c by the alloxan radical. Implications for alloxan cytotoxicity. Biochem J 207: 609
Zweier JL (1984) Reduction of O2 by iron-Adriamycin. J Biol Chem 159: 6056
Zweier JL (1985) Iron-mediated formation of an oxidized adriamycin free radical. Biochim Biophys Acta 839: 209
Zweier JL, Gianni L, Muindi J, Myers CE (1986) Differences in O2 reduction by the iron complexes of adriamycin and daunomycin: the importance of the sidechain hydroxylgroup. Biochim Biophys Acta 884: 326
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hüsken, B.C.P., de Jong, J., Beekman, B. et al. Modulation of the in vitro cardiotoxicity of doxorubicin by flavonoids. Cancer Chemother. Pharmacol. 37, 55–62 (1995). https://doi.org/10.1007/BF00685629
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00685629