Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death

Abstract

Background: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions. Methods: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg −1 weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. Results: Dexrazoxane (60 mg kg −1 ) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. Conclusion: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

“…However, the DEX/ ANT ratio and dosing interval could have been suboptimal in this study. It has been also demonstrated that DEX pretreatment (20:1) is able to very effectively prevent the onset of both degenerative changes and apoptotic cell death induced by chronic ANT treatment in rabbits (DAU 3 mg/kg, weekly for 10 weeks) (208). DEX treatment rescued cardiomyocytes from complex proapoptotic signaling, and resulting cell death and parameters of apoptosis correlated well with the cardiotoxicity parameters.…”

“…Surprisingly, effective cardioprotection with DEX was not associated with significant decrease of moderately elevated markers of lipoperoxidation. In addition, no correlation has been found between myocardial malondialdehyde levels and parameters of cardiac function (208).…”

“…The latter event may be also triggered by the proapoptotic Bcl-2 family proteins creating nonselective channels in the mitochondrial membrane. Indeed, clinically relevant doses and concentrations of ANTs have been repeatedly shown to activate apoptotic pathways (8,196,208,226,301), and successful cardioprotection with DEX has reduced this process (208). Hence, mitochondrial oxidative stress as well as other above-described events may trigger apoptotic cell death, which may be coresponsible for CHF development.…”

Chronic Anthracycline Cardiotoxicity: Molecular and Functional Analysis with Focus on Nuclear Factor Erythroid 2-Related Factor 2 and Mitochondrial Biogenesis Pathways

“…The study was performed by using the previously well established animal model of chronic ANT cardiotoxicity (Š imů nek et al, 2004;Popelová et al, 2009;Š těrba et al, 2011). Adult male Chinchilla rabbits (ϳ4 months old; ϳ3.5 kg; n ϭ 46; Velaz, Koleč u Kladna, Czech Republic) were housed under a 12-h light cycle with constant temperature and humidity and free access to tap water and a standard laboratory pellet diet.…”

Experimental determination of diagnostic window of cardiac troponins in the development of chronic anthracycline cardiotoxicity and estimation of its predictive value

“…Significant elevation of cTns (both cTnT and cTnI) has been observed in many experimental models of chronic ANT cardiotoxicity [9][10][11] and the majority of data show that they could be an early marker that rises before the deterioration of LV systolic function [12][13][14]. Scattered data in the literature, including our own [15][16][17], has suggested that ANT-induced cardiac damage is associated with a relatively prolonged release of cTns, but further details are lacking.…”