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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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Representative samples of left ventricular (LV) myocardium showing 4-hydroxynonenal staining in the control (A), DAU (B) and DEX+DAU (C) groups.
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fig8: Representative samples of left ventricular (LV) myocardium showing 4-hydroxynonenal staining in the control (A), DAU (B) and DEX+DAU (C) groups.

Mentions: The immunohistochemical detection of 4-HNE (another independent marker of lipoperoxidation) in the LV myocardium revealed a markedly higher response in the samples obtained from DAU-treated animals than in corresponding controls (Figure 8A and B). The 4-HNE signal was predominantly detected within the cardiomyocytes, whereas interstitial cells showed poor immunoreactivity. The myocardium of DEX co-treated animals (Figure 8C) showed a 4-HNE signal intensity that was largely comparable with that in the DAU-alone group. Although in some cases a moderate degree of reduction of the 4-HNE signal could be found in the DEX+DAU group, it was clearly always very far from being complete. No distinct changes in 4-HNE signal localisation could be found between the DAU and DEX+DAU groups.


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)

Representative samples of left ventricular (LV) myocardium showing 4-hydroxynonenal staining in the control (A), DAU (B) and DEX+DAU (C) groups.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Representative samples of left ventricular (LV) myocardium showing 4-hydroxynonenal staining in the control (A), DAU (B) and DEX+DAU (C) groups.
Mentions: The immunohistochemical detection of 4-HNE (another independent marker of lipoperoxidation) in the LV myocardium revealed a markedly higher response in the samples obtained from DAU-treated animals than in corresponding controls (Figure 8A and B). The 4-HNE signal was predominantly detected within the cardiomyocytes, whereas interstitial cells showed poor immunoreactivity. The myocardium of DEX co-treated animals (Figure 8C) showed a 4-HNE signal intensity that was largely comparable with that in the DAU-alone group. Although in some cases a moderate degree of reduction of the 4-HNE signal could be found in the DEX+DAU group, it was clearly always very far from being complete. No distinct changes in 4-HNE signal localisation could be found between the DAU and DEX+DAU groups.

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