Deferiprone Does Not Protect against Chronic Anthracycline Cardiotoxicity in Vivo

Popelová, Olga; Štěrba, Martin; Šimůnek, Tomáš; Mazurová, Y; Gunčová, Ivana; Hroch, Miloš; Adamcová, Michaela; Geršl, Vladimír

doi:10.1124/jpet.108.137604

Cited by 46 publications

(31 citation statements)

References 42 publications

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“…Myocardial oxidative damage due to iron-mediated ROS formation has been suggested as a potential mechanism, but the "ROS and iron hypothesis" has been challenged by reports that several iron chelators fail to reverse the cardiotoxic effects of DOX (4). Our data suggest that DOX cardiotoxicity develops from the specific accumulation of iron in the mitochondria and that DXZ, which can effectively effective iron chelators, deferiprone and deferasirox, also fail to protect against DOX-induced cardiac damage (39,40), and aroylhydrazone Fe chelators (e.g., pyridoxal isonicotinoyl hydrazone and its analogs), which are small lipophilic molecules, provide less protection than DXZ against DOX toxicity as well (4). This discrepancy in the effects of different iron chelators could be due to their varying effectiveness in reducing mitochondrial iron, which we demonstrate here for DFO and DXZ.…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

721

559

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Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

721

559

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“…as protectors against ANT-induced cardiotoxicity in vitro and/or in vivo (see below), have been also shown not to blunt the antiproliferative effects of ANTs in various cancer cell lines (209,243,256). It should be noted that-with the exception of few DEX analogs (108)-no chelator has been specifically designed for use in prevention of ANT cardiotoxicity.…”

mentioning

confidence: 99%

“…Hence, several lines of evidence indicated that L1, being already a clinically approved drug, might be a promising and readily available option to increase the cardiac safety of cancer patients undergoing treatment with ANTs. Nevertheless, in a study on a clinically relevant and DEXvalidated model of chronic ANT-induced cardiotoxicity in rabbits (239), L1 showed no potential to alleviate either ANTinduced oxidative stress or the LV cardiac damage and CHF, as assessed by both echocardiography and LV catheterization (209). L1 was administered orally in two doses of 10 and 50 mg/kg, 45 min before each DAU injection (3 mg/kg i.v.…”

mentioning

confidence: 99%

“…L1 was administered orally in two doses of 10 and 50 mg/kg, 45 min before each DAU injection (3 mg/kg i.v. ), and the higher L1 dose (50 mg/kg, well tolerated when administered alone) actually led to earlier animal deaths (209). The doses and timing of L1 administration were specifically designed according to the pharmacokinetic study performed in rabbits (65) to achieve and maintain drug concentrations affording significant protection against ANT cardiotoxicity in vitro (10,65).…”

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confidence: 99%

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

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

Self Cite

277

192

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“…One of the alleged causes of doxorubicin cardiomyopathy is related to the effect on iron metabolism: Anthracyclines are bound to Fe 2+ ions, which leads to the development of a hydroxyl radical and promotes the release of Fe 2+ ions from ferritin, exacerbating oxidative stress. [11] Therefore, if cell cytoplasm demonstrates the conditions for chelating or the oxidation of ferrous ions Fe 2+ in a catalytically inactive state of Fe 3+ ions, thus leading to the decrease of current hydroxyl radical concentration, this will create the conditions for micromolar AOS concentrations in cell cytoplasm. [12,13] The substances with antioxidant activity play an important role in the regulation of free-radical mechanisms.…”

Section: Results and Its Discussionmentioning

confidence: 99%

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Даниленко

2017

AJP

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Introduction: The search for new compounds with cardioprotective activity among the derivatives of 5-hydroxynicotinic acid is promising. Objectives: The objective of this study is to study the cardioprotective effects of the derivatives from 5-hydroxynicotinic acid SSC-77 (K-5-hydroxynicotinic acid) and SSC-497 (Mg-5-hydroxynicotinica acid). Methods: The cardioprotective effect of SSC-77 and SSC-prisocorubicin (20 mg/kg, intraperitoneally for 48 h) pathology was assessed by the results of the functional test with high-frequency stimulation (480 bpm). The research of myocardial resistance to ischemia/reperfusion injury was studied according to hypo-reperfusion model on an isolated rat heart on the record of pressure in the left ventricle. The isoenzyme creatine phosphokinase (KFK-MB) and lactate dehydrogenase (LDH) were determined for the complex evaluation of myocardial damage in the flowing off perfusate from isolated hearts. The activity of lipid peroxidation (LPO) was assessed by the content of malondialdehyde (MDA) and diene conjugates (DC). Results: SSC-77 (27.6 mg/kg/day) and SSC-497 (58.1 mg/kg/day) show a cardioprotective effect using the doxorubicin pathology model, which is expressed in the decrease of diastolic dysfunction coefficient (S tТTI ) to 2.1 ± 0.2 r.u. and 3.3 ± 0.1 r. units, respectively, as compared with the control group 8.3 ± 0.1 r. un. Using the model of hypo-reperfusion, the substances SSC-77 (10 −6 mol / l) and SSC-497 (10 −6 mol / l) prevent the decrease of contractility indices on the 5 th and 20 th min during the reperfusion period in comparison with the control where the fall made 50%. The cardioprotective effect was confirmed by 47% and 39% decrease concerning the levels of KFK-MB marker damage by 39% and 47% and LDH by 21.8% and 19.6%, respectively, in the series with SSC-77 and SSC-497 in comparison with the control group, as well as by the prevention of LPO products MDA and DC accumulation in the ventricular myocardium. Conclusion: The derivatives of 5-hydroxynicotinic acid SSC-77 and SSC-497 reduce diastolic dysfunction, prevent the decrease of cardiac functional activity after ischemia/reperfusion, reduce the irreversible damage of cardiomyocytes, and have antioxidant properties.

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Deferiprone Does Not Protect against Chronic Anthracycline Cardiotoxicity in Vivo

Cited by 46 publications

References 42 publications

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

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

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