Doxorubicin‐Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy

Carvalho, Filipa S.; Burgeiro, Ana; Garcia, Rita; Moreno, António J.; Carvalho, Rui A.; Oliveira, Paulo J.

doi:10.1002/med.21280

Cited by 461 publications

(375 citation statements)

References 201 publications

(277 reference statements)

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“…Cardiomyocyte loss through cell death pathways is a customary paradigm to explain functional deficits in the heart, and there is ample experimental evidence to support DOX‐induced apoptosis, necrosis and autophagy, as reviewed by Carvalho et al (2014). One of the major theories of the action of DOX is based on its interference with iron metabolism and generation of excess of ROS.…”

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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“…2 Doxorubicin has been the part of highly effective chemotherapeutic regimens for more than 30years for the treatment of a wide variety of cancers including bladder, breast, lung, stomach, and ovarian cancers, Hodgkin's and non-Hodgkin's lymphomas, certain types of leukemias, multiple myelomas, gastric, thyroid carcinomas, soft tissue sarcomas, osteosarcoma, neuroblastoma, nephroblastoma, Kaposi's sarcoma and Wilms tumour. 3 The clinical success of doxorubicin is usually limited due to the development of many adverse side effects including myelosuppression, nausea, vomiting, mouth ulcers, local aggressivity, alopecia, hallucinations, vertigo, dizziness, bone marrow aplasia and life threatening cardiotoxicity. 4 Doxorubicin treatment also causes hypersensitivity (fever, chills, and urticaria), hyperpigmentation of the nails, lacrimation and conjunctivitis.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Ch¹,

Jagetia²,

Lalrinengi³

2017

MOJAP

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Doxorubicin a photosensitive antibiotic is frequently used to treat various malignancies in clinics; however, doxorubicin is also taken up by the normal cells of the body leading to increased oxidative stress and subsequently DNA damage and dysfunction in the cells. The agents which can reduce the adverse effect of doxorubicin will of great value. The present study has attempted to study the effect of naringin a citrus flavonoid on the doxorubicininduced oxidative stress in mice liver. The mice were administered with 0, 1, 5 or 10mg/ kg body weight of doxorubicin and treated with 10mg/kg body weight of naringin before or after doxorubicin treatment. The glutathione concentration and lipid peroxidation and activities of glutathione-s-transferase, catalase and super oxide dismutase were studied at 0.5, 1, 2 and 4h post-treatment in the mouse liver. The doxorubicin increased the lipid peroxidation in a dose dependent manner at all the post treatment times. Conversely, it attenuated the activities of glutathione-s-transferase, catalase and super oxide dismutase in dose dependent fashion and time dependent manner. A similar effect was observed for glutathione concentration. Treatment of mice with naringin before or after doxorubicin treatment elevated all the antioxidants and reduced the doxorubicin -induced lipid peroxidation. The effect of naringin pretreatment was more effective when compared to its post treatment. The naringin was very effective in reducing the oxidative stress induced by doxorubicin as indicated by the elevated levels of glutathione concentration, glutathiones-transferase, catalase and super oxide dismutase. The pretreatment of naringin was better than its post treatment.

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“…The mechanism of DOX's cardiotoxicity is complex and may involve oxidative (2,3), nitrosative and nitrative stress (4,5), mitochondrial dysfunction/ toxicity (1,(6)(7)(8), dysregulation of various metabolic (9) and lipid signaling pathways (10)(11)(12), activation of various stress kinases and cell death mechanisms (both apoptotic and necrotic) (13), triggering of secondary inflammation and remodeling (14), eventually culminating in cardiac dysfunction and heart failure (1,15).…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Hao

Mukhopadhyay

Cao

et al. 2015

Mol Med

128

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Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

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Doxorubicin‐Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy

Cited by 461 publications

References 201 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

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

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