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

Štěrba, Martin; Popelová, Olga; Vávrová, Anna; Jirkovský, Eduard; Kovařı́ková, Petra; Geršl, Vladimír; Šimůnek, Tomáš

doi:10.1089/ars.2012.4795

Cited by 277 publications

(205 citation statements)

References 278 publications

(311 reference statements)

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“…One of the major theories of the action of DOX is based on its interference with iron metabolism and generation of excess of ROS. However, although antioxidants, such as co‐enzyme Q10, N‐acetylcysteine and vitamins C and E, have been reported to exert cardioprotective effects in experimental models (Sterba et al, 2013), the results of small randomized clinical trials have not shown clear benefit (van Dalen et al, 2011; Vincent et al, 2013). The lack of success of antioxidant therapeutic strategies is likely to demonstrate the complexity of redox reactions in biological tissues (Madamanchi and Runge, 2013), in which ROS are known to serve both physiological and maladaptive roles.…”

Section: Introductionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Introductionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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“…18 So far, iron chelation is the only pharmacological intervention against either iron-induced cardiac failure or anthracycline-induced cardiotoxicity (mediated by the imbalance iron homeostasis). 25 But the progress in this area is lagged by the lack of effective agents. Numerous agents tested so far, only a few are currently in further development.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection Potential of Some Hydroxypyridine Iron Chelators Against H2O2-Induced H9C2 Cell Injury

Behjati¹,

Fassihi²,

Dehkordi³

et al. 2017

Turkiye Klinikleri J Cardiovasc Sci

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A AB BS S T TR RA AC CT T O O b bj je ec ct ti iv ve e: : Iron-induced cardiotoxicity serves as the main cause of heart failure in young adults and is formidable in many patients. Intracellular iron chelation either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron is the only well-established strategy for cardioprotection. We aimed to evaluate the cardioprotective role of some hydroxypyridine derivative iron chelators on rat myoblast cell line. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : Five different derivatives of the 3-hydroxypyridine-4-one scaffold were prepared according a previously reported study. Compounds (10-100 μM) or L1 as standard iron chelator (30-100 μM) dissolved in dimethyl sulfoxide and applied to dulbecco's minimal essential medium (DMEM) culture medium 1 h prior and during H 2 O 2 (100 μM) exposure. H9C2 cells were exposed with FeSO4 (3-30 μM). R Re es su ul lt ts s: : Cell survival studies were evaluated through lactate dehydrogenase (LDH) leakage and Annexin-V/ propidium iodide counter staining. Application of iron chelators in the culture media of injured H9C2 cells resulted in non-significant decrease in the amounts of released LDH. Indeed, these compounds were not associated with significant induction of cell death through apoptosis, necrosis or both. C Co on nc cl lu us si io on n: : The present study demonstrates that these hydroxypyridine derivatives have no effect on nullifying H 2 O 2 -induced oxidative stress on in vitro model of cardiac injury. K Ke ey yw wo or rd ds s: : Iron chelating agents; myoblasts, cardiac; cells, cultured Ö ÖZ ZE ET T A Am ma aç ç: : Genç bireylerde kalp yetmezliğinin ana nedeni olan demir-nedenli kardiyotoksite, birçok hastada yönetilebilir bir durumdur. Kalbin korunması için, hasarlı hücrelerde demir homeostazını sağlamak üzere hem intraselüler demir şelasyonu düzenlenmeli hem de redoks-aktif demirin uzaklaştırılması en iyi stratejidir. Biz, rat miyoblast hücre hattında bazı hidroksipiridin türevi demir bağlayıcıların kardiyoprotektif etkilerini inceledik. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Bir önceki çalışmamızda bildirdiğimiz şekilde hazırladığımız, 3-hidroksipiridin-4-one çatı molekülünün 5 farklı türevlerini kullandık. 10-100 µM bileşikleri veya L1 standart demir bağlayıcılar (30-100 µM), dimetil sülfok-sit içinde çözündürülüp, dulbecco minimum esansiyel vasat (DMEM) kültür kabına, H 2 O 2 (100 µM) ile maruziyet sırasında ve maruziyetten 1 saat önce eklendi. H9C2 hücreleri FeSO 4 (3-30 µM) ile muamele edildi. B Bu ul lg gu ul la ar r: : Hücre sağkalım çalışmaları laktat dehidrogenaz (LDH) salınımı ve Anneksin-V/propidium iyot boyanma sayımı üzerinden değerlendirildi. Hasarlı H9C2 hücreleri içe-ren kültür ortamına demir bağlayıcıların eklenmesi LDH salınım miktarlarında önemli olmayan azalma sağladı. Gerçekte bu bileşikler apoptozis, nekrozis veya her ikisi üzerinden hücre ölümünün önemli şekilde indüklenmesi ile bağlantılı değildi. S So on nu uç ç: : Çalışmamızın sonuçlarına gör...

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“…DXR is currently used for cardioprotection in patients clinically treated with anthracyclines (see for reviews [ 1 , 6 , 13 ]). Its cardioprotective effect is usually attributed to its rings-opened metabolites resulting from enzymatic hydrolysis, which exhibit iron chelation properties [ 6 ]. We used here DXR for its presumed antioxidant activity as it is believed that DXR metabolites attenuate the iron-dependent oxidative stress mediated by anthracyclines.…”

Section: Figmentioning

confidence: 99%

“…Although a matter of debate [ 1 ], DOX cardiotoxicity is thought to be due to induction of apoptosis [ 5 , 8 -10 ] resulting from oxidative stress [ 5 , 6 , 9 , 11 , 12 ]. The clinical use of compounds that detoxify ROS has been advocated as adjunctive therapy [ 6 ]. Accordingly, the bisdioxopiperazine agent dexrazoxane (DXR) showed a successful cardioprotection in the clinical setting [ 5 , 6 , 13 ] that was proposed to result from its metabolic bioactivation into rings-opened metal ion-chelating forms that display an antioxidant activity [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells

et al. 2016

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The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2 µM DOX 1 day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24 h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro.

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

Cited by 277 publications

References 278 publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Cardioprotection Potential of Some Hydroxypyridine Iron Chelators Against H2O2-Induced H9C2 Cell Injury

Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells

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