Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats

Thompson, Karol L.; Rosenzweig, Barry A.; Zhang, Jun; Knapton, Alan; Honchel, Ronald; Lipshultz, Steven E.; Retief, Jacques D.; Sistare, Frank D.; Herman, Eugene H.

doi:10.1007/s00280-009-1164-9

Cited by 61 publications

(37 citation statements)

References 33 publications

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“…Hence, increased protection against MOMP after DOX exposure, and hence a counter-priming, is indicated by elevation of the anti-apoptotic protein BCL2 [23], by an increase of BCL2/BAX protein ratio [57] and elevation of the anti-apoptotic gene ARC in rat hearts [58,59]. As most of these studies were performed in whole hearts, further studies will reveal to what extent DOX primes or anti-primes cardiomyocytes to further pre-or post-MOMP apoptosis or to apoptosis susceptibility to cell death ligands.…”

Section: Does Dox Exposure Change Apoptosis Likelihood To Later Somatmentioning

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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Section: Does Dox Exposure Change Apoptosis Likelihood To Later Somatmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane, together with chemotherapy, reduces the expression of the NRF-2 gene (responsible for oxidative stress response), which is overexpressed in patients receiving ANT alone (2). We previously identified an epirubicin (EPI)-induced early myocardial dysfunction, detected after a low dose (200 mg/ m 2 ) of EPI (7).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane, together with chemotherapy, reduces the expression of the NRF-2 gene (responsible for oxidative stress response), which is overexpressed in patients receiving ANT alone (2).…”

Section: Introductionmentioning

confidence: 99%

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Dessì

Piras

Madeddu

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular diseasefree with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m 2 of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t 2 (cumulative dose of 200 mg/m 2 of EPI) in comparison to t 0 . Conversely, at t 3 (300 mg/m 2 EPI), t 4 (400 mg/m 2 EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t 0 (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m 2 EPI (t 3 ) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m 2 EPI (t 2 ) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t 2 vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t 2 was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t 2 in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress. IntroductionAnthracyclines (ANTs) are among the most effective anticancer drugs used in the treatment of a wide spectrum of malignancies. Regrettably, their clinical use is limited by the occurrence of dose-related cardiotoxicity (4).Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane,

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“…On the other hand, it has also been reported that some pathological cardiac dysfunctions such as hypertrophy were associated with the up-regulation of fetal genes such as atrial natriuretic factor (ANF) and isoforms of myosin heavy chain (MHC) (Ritter and Neyses, 2003;van den Bosch et al, 2006). Early alterations in heart gene expression profiles associated with cardiotoxicity have been studied in vitro and in vivo (Thompson et al, 2010). Using microarrays, Berthiaume and Wallace (2007) studied global gene expression changes occurring in rats' hearts 5 weeks after subchronic DOX treatment.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress and Myocardial Gene Alterations Associated with Doxorubicin-Induced Cardiotoxicity in Rats Persist for 2 Months after Treatment Cessation

Richard¹,

Ghibu²,

Delemasure-Chalumeau³

et al. 2011

J Pharmacol Exp Ther

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The molecular mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy include alterations in cardiomyocytes' oxidative stress status and in gene expression. Although such alterations have been reported during in vivo DOX treatment of animals, it remains to be clarified whether they persist after treatment cessation. To address this question, rats were injected with either saline (1 ml/kg/day i.p; control) or DOX (1 mg/kg/day i.p.) for 10 days, and 70 days later cardiac functional parameters were evaluated in vivo by left ventricular catheterization. Hearts were also harvested for histological analyses as well as measurements of oxidative stress parameters by various techniques and gene expression by quantitative polymerase chain reaction of markers of cardiac pathological remodeling, namely atrial natriuretic factor, myosin heavy chain ␤, vascular endothelial growth factor A (VEGF-A), and sarcoplasmic reticulum Ca ϩ2 ATPase. Compared with controls, DOXtreated rats displayed marked alterations in most parameters even 2 months after cessation of treatment. These included 1) lower left ventricular contractility (ϩdP/dt), 2) increased levels of plasma and myocardial oxidative stress markers, namely thiobarbituric acid reactive substances or dihydroethidium fluorescence, and 3) markedly altered transcript levels for all measured markers of cardiac remodeling, except VEGF-A. These changes correlated significantly with ϩdP/dt values assessed in the two groups of animals. In conclusion, this study demonstrated that as many as 2 months after cessation of DOX treatment cardiac alterations persisted, reflecting increased oxidative stress and pathological remodeling, the latter being linked to the development of contractile dysfunction.

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Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats

Cited by 61 publications

References 33 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Oxidative Stress and Myocardial Gene Alterations Associated with Doxorubicin-Induced Cardiotoxicity in Rats Persist for 2 Months after Treatment Cessation

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