Anthracycline-related cardiotoxicity in childhood cancer survivors

Lipshultz, Steven E.; Karnik, Ruchika; Sambatakos, Peter; Franco, Vivian I.; Ross, Samuel W.; Miller, Tracie L.

doi:10.1097/hco.0000000000000034

Cited by 75 publications

(52 citation statements)

References 86 publications

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“…DOX is a widely used and successful anti-tumor drug; however, its clinical use is limited due to its severe cumulative dose-associated cardiotoxicity (2). Numerous studies have demonstrated that the primary molecular mechanism involved in DOX-induced cardiotoxicity is free radical-induced oxidative stress, and cardiomyocyte death by apoptosis and necrosis (5,22).…”

Section: Discussionmentioning

confidence: 99%

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Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes

Liu

Shan

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Doxorubicin (DOX) is an efficient drug used in cancer therapy; however, it can induce severe cytotoxicity, which limits its clinical application. In the present study, the effects of resveratrol (RES) on sirtuin 1 (SIRT1) activation in mediating DOX-induced cytotoxicity in H9c2 cardiac cells was investigated. H9c2 cells were exposed to 5 µM DOX for 24 h to establish a model of DOX cardiotoxicity. Apoptosis of H9c2 cardiomyocytes was assessed using the MTT assay and Hoechst nuclear staining. The results demonstrated that pretreating H9c2 cells with RES prior to the exposure of DOX resulted in increased cell viability and a decreased quantity of apoptotic cells. Western blot analysis demonstrated that DOX decreased the expression level of SIRT1. These effects were significantly alleviated by co-treatment with RES. In addition, the results demonstrated that DOX administration amplified forkhead box O1 (FoxO1) and P53 expression levels in H9c2 cells. RES was also found to protect against DOX-induced increases of FoxO1 and P53 expression levels in H9c2 cells. Furthermore, the protective effects of RES were arrested by the SIRT1 inhibitor nicotinamide. In conclusion, the results demonstrated that RES protected H9c2 cells against DOX-induced injuries via SIRT1 activation.

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Section: Discussionmentioning

confidence: 99%

“…However, the clinical use of this valuable anticancer drug is limited by severe toxic side effects on the heart, which may result in heart failure (2). Numerous studies have implicated reactive oxygen species generation in the cardiotoxicity of DOX, which ultimately results in cardiomyocyte apoptosis (3,4).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes

Liu

Shan

et al. 2016

Experimental and Therapeutic Medicine

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“…Pathologically, doxorubicin-induced cardiomyopathy was associated with heightened oxidative stress status, apoptosis of cardiac cells, inflammatory response, myocardial fibrosis, metabolism abnormality, DNA damage and mitochondrial damage [3–7]. Several agents including anti-oxidants, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB) and dexrazoxan have been employed for the attenuation of doxorubicin-induced cardiomyopathic damage [8, 9]. Unfortunately, all of these agents have not yet gained effective enough evidence to justify a routine use.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats

Kong

Wang

et al. 2017

Oncotarget

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Angiotensin-converting enzyme 2 (ACE2) is considered a potential therapeutic target of the renin-angiotensin system (RAS) for the treatment of cardiovascular diseases. We aimed to explore the effects of ACE2 overexpression on doxorubicin-induced cardiomyopathy in rats. Rats were randomly divided into treatment and control groups. The rats of treatment group were injected intraperitoneally with 6 doses of doxorubicin (2.5 mg/kg) within a period of two weeks. Two weeks after the initial injection of doxorubicin, these rats were randomly divided into Mock, Ad-EGFP, Ad-ACE2, and Cilazapril groups. The rats of Ad-EGFP and Ad-ACE2 groups received intramyocardial injection of Ad-EGFP and Ad-ACE2, respectively. The rats of Cilazapril group received cilazapril (10 mg/kg/day) via intragastric intubation. Apoptosis, inflammation, oxidative stress, cardiac function, the extent of myocardial fibrosis, and levels of ACE2, ACE, angiotensin II (AngII), and angiotensin (1–7) were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed not only reduced apoptosis, inflammatory response, oxidative stress, left ventricular (LV) volume, extent of myocardial fibrosis and mortality of rats, but also increased LV ejection fraction and ACE2 expression level compared with the Mock and Ad-EGFP groups. ACE2 overexpression was superior to cilazapril in improving doxorubicin-induced cardiomyopathy. The putative mechanisms may involve activation of the AMPK and PI3K-AKT pathways, inhibition of the ERK pathway, decrease of TGF-β1 expression, and interactions of shifting RAS components, such as decreased myocardium AngII levels, increased myocardium Ang (1–7) levels, and reduced ACE expression. Thus, ACE2 may be a novel therapeutic approach to prevent and treat doxorubicin-induced cardiomyopathy.

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“…Chronic DCM leads to cardiac dysfunction and eventually congestive heart failure, resulting in the need for heart transplant or even causing death [7]. Chronic DCM occurs in about 10-20% of cancer survivors often 10-15 years following treatment [3,8,9]. As the likelihood of DCM cannot be assessed a priori for an individual patient, the usual dosage of DOX is usually restricted to 60-75 mg/m² every 3 weeks, hence limiting its efficacy [10].…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Anthracycline-related cardiotoxicity in childhood cancer survivors

Cited by 75 publications

References 86 publications

Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes

Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes

Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

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