Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro

Spallarossa, Paolo; Garibaldi, Silvano; Altieri, Paola; Fabbi, Patrizia; Manca, Valeria; Nasti, Sabina; Rossettin, Pierfranco; Ghigliotti, G; Ballestrero, Alberto; Patrone, Franco; Barsotti, Antonio; Brunelli, Claudio

doi:10.1016/j.yjmcc.2004.05.024

Cited by 267 publications

(184 citation statements)

References 39 publications

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“…Evidences that DOX exposure can lead to apoptosis sensitization similar to cancer cell priming comes a study which found a decrease in mRNA expression of the anti-apoptotic BCL-2 and increase of pro-apoptotic BAX [56]. Likewise, in the aforementioned study of Zhang an upregulation of mRNA transcripts was found for the pro-apoptotic gene APAF-1, BAX and FAS-L after DOX exposure in mice with wild type TOP-2.…”

Section: Does Dox Exposure Change Apoptosis Likelihood To Later Somatmentioning

confidence: 90%

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: 90%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…The group showed that CAR reduced cellular vacuolization in cardiac myocytes and prevented doxorubicin's inhibitory effect on mitochondrial respiration in both heart and liver cells. There are many reports on the protective effect of CAR on mitochondria via its antioxidant property (27)(28)(29)(30). Similar to doxorubicin, IM's inhibitory effect on mitochondria has been proven with several findings, including those from the cardiotoxicity and cancer studies identifying mitochondria as a chief target of IM (31,32).…”

Section: Discussionmentioning

confidence: 99%

Carvedilol in glioma treatment alone and with imatinib in vitro

Ergüven

Yazıhan

Aktaş³

et al. 2010

Int J Oncol

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Abstract. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 μM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number, BrDU-LI, cAMP levels and spheroid volume. Carvedilol and imatinib mesylate arrested cells at G0/ G1 phase in a time-dependent manner and time-independent manner, respectively. Carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.

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“…Doxorubicin (DOX)-induced cardiotoxicity was related to the activation of apoptosis in cardiomyocytes and endothelial cells (Wu et al, 2002;Yamanaka et al, 2003;Spallarossa et al, 2004). In these cells the main effects of DOX were mediated via the production of ROS, known for its potent cell damaging effects.…”

Section: Discussionmentioning

confidence: 99%

“…Doxorubicin (DOX)-induced ROS have been shown as the primary cause of the heart damaging effect of the drug (Horenstein et al, 2000;Xu et al, 2001). In addition, several studies suggested that DOX-induced apoptosis in endothelial cells and cardiomyocytes contributes to the development of DOX-related cardiotoxicity (Childs et al, 2002;Wu et al, 2002;Kluza et al, 2004;Spallarossa et al, 2004). Various strategies have been developed to protect against DOX-induced cardiotoxic effects.…”

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confidence: 99%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro

Cited by 267 publications

References 39 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Carvedilol in glioma treatment alone and with imatinib in vitro

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

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