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

Popelová O, Sterba M, Hasková P, Simůnek T, Hroch M, Guncová I, Nachtigal P, Adamcová M, Gersl V, Mazurová Y - Br. J. Cancer (2009)

Bottom Line: 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.However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.

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.

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Related in: MedlinePlus

(A) Echocardiographically determined left ventricular (LV) fractional shortening (FS) during the time course of experiment. (B) Invasively determined index of LV contractility (index dP/dtmax) at the end of the experiment. Statistical significance in comparison with ‘*' the initial values within each group (paired t-test, P<0.05), ‘c' control, ‘d' daunorubicin and ‘x' DEX+DAU groups (ANOVA, P<0.05).
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fig1: (A) Echocardiographically determined left ventricular (LV) fractional shortening (FS) during the time course of experiment. (B) Invasively determined index of LV contractility (index dP/dtmax) at the end of the experiment. Statistical significance in comparison with ‘*' the initial values within each group (paired t-test, P<0.05), ‘c' control, ‘d' daunorubicin and ‘x' DEX+DAU groups (ANOVA, P<0.05).

Mentions: Echocardiographically determined FS revealed a progressive and significant decline in LV systolic function in DAU-treated animals, starting by the eighth week (Figure 1A). In addition, an impaired LV systolic performance was also found in this group by invasive contractility examination performed at the end of the study (Figure 1B). In contrast, animals receiving DEX before each DAU injection showed nearly the same systolic function as the controls, which was evident from the outcomes of both types of the LV systolic examination (Figure 1A and B).


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

Popelová O, Sterba M, Hasková P, Simůnek T, Hroch M, Guncová I, Nachtigal P, Adamcová M, Gersl V, Mazurová Y - Br. J. Cancer (2009)

(A) Echocardiographically determined left ventricular (LV) fractional shortening (FS) during the time course of experiment. (B) Invasively determined index of LV contractility (index dP/dtmax) at the end of the experiment. Statistical significance in comparison with ‘*' the initial values within each group (paired t-test, P<0.05), ‘c' control, ‘d' daunorubicin and ‘x' DEX+DAU groups (ANOVA, P<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736842&req=5

fig1: (A) Echocardiographically determined left ventricular (LV) fractional shortening (FS) during the time course of experiment. (B) Invasively determined index of LV contractility (index dP/dtmax) at the end of the experiment. Statistical significance in comparison with ‘*' the initial values within each group (paired t-test, P<0.05), ‘c' control, ‘d' daunorubicin and ‘x' DEX+DAU groups (ANOVA, P<0.05).
Mentions: Echocardiographically determined FS revealed a progressive and significant decline in LV systolic function in DAU-treated animals, starting by the eighth week (Figure 1A). In addition, an impaired LV systolic performance was also found in this group by invasive contractility examination performed at the end of the study (Figure 1B). In contrast, animals receiving DEX before each DAU injection showed nearly the same systolic function as the controls, which was evident from the outcomes of both types of the LV systolic examination (Figure 1A and B).

Bottom Line: 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.However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.

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.

Show MeSH
Related in: MedlinePlus