Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress

Marques‐Aleixo, Inês; Santos‐Alves, Estela; Mariani, Diogo; Rizo‐Roca, David; Padrão, Ana Isabel; Rocha-Rodrigues, Sílvia; Viscor, Ginés; Torrella, Joan Ramón; Ferreira, Rita; Oliveira, Paulo J.; Magalhães, José; Ascensão, António

doi:10.1016/j.mito.2014.10.008

Cited by 86 publications

(72 citation statements)

References 55 publications

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“…In agreement with previous reports (29), DOX treatment tended to decrease cardiac mitochondrial complex I activity, whereas VEGF-B treatment increased the activity. This is consistent with our previous data showing that VEGF-B protects against ischemia reperfusion-induced mitochondrial dysfunction (11).…”

Section: Discussionsupporting

confidence: 93%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

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Section: Discussionsupporting

confidence: 93%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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“…In six studies, 15,16,20,22,23,26 the DOX dose was 10 mg/kg. Chicco et al 9 found that exercise provides resistance against cardiac dysfunction and oxidative damage associated with DOX.…”

Section: Treatment Protocolsmentioning

confidence: 99%

“…[10][11][12][13][14][15]17,18,20,[22][23][24][25]27 . A study 7 on male rats aimed to determine whether physical exercise had a cardioprotective effect on juvenile rats treated with DOX.…”

Section: Introductionmentioning

confidence: 99%

Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review

Maia

Araujo

Teixeira

et al. 2017

International Journal of Cardiovascular Sciences

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The present study investigated whether the practice of exercise has a protective effect against cardiac toxicity induced by doxorubicin (DOX). A systematic review of randomized clinical trials evaluating the role of exercise in the control or prevention of DOX-induced cardiotoxicity was performed in MEDLINE and LILACS databases. Studies that did not address the main subject of this review, did not mention physical exercise or DOX, studies that evaluated other types of anthracycline-induced toxicities only (muscle, hepatic and renal toxicity) or other effects of exercise on DOX toxicity (fatigue) were excluded. With respect to the variables related to aerobic exercise prescription, there was no direct relationship between the frequency of exercise and the results of the studies. Also, intensity of exercise was not decisive for preservation of cardiac function, although a more intense exercise was associated with improvements in the antioxidant system, which was not observed in studies on lower intensity exercises. No significant differences in exercise effects were observed when it was performed before, during or after the treatment. Therefore, aerobic exercise may exert a protective effect of cardiac functions when performed before, during or after treatment with DOX. However, the mechanisms of this effect are still unknown.

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“…However, the exact mechanism of DOX-induced cardiac stress remained unclear. Nevertheless, a large body of evidence indicates the formation of oxygen free radicals, which can damage cells through lipid peroxidation (7,29). Free radicals are continuously produced in vivo, and there are a number of protective antioxidant enzymes (SOD, catalase, etc.)…”

Section: / Hashemi Chashmi and Colleaguesmentioning

confidence: 99%

“…Most studies confirm that oxidative stress plays an important role in the pathogenesis of DOX-induced toxicity (4,5). Several mechanisms have been proposed to be attributed for the DOX-induced cardiotoxicity including free radicals, lipid peroxidation, mitochondrial damage and cellular toxicity (6,7). The overproduction of free radicals and oxidative stress in violation of anti-oxidants plays a main role in the development of DOXinduced tissue damage (8,9).…”

Section: Introductionmentioning

confidence: 99%

Age-Related Changes in Doxorubicin-Induced Oxidative Damage: Protective and Pretreatment Effects of Short-Term Aerobic Exercise

Chashmi¹,

Roshan²,

Azizi³

2016

mljgoums

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Background and Objective: Doxorubicin (DOX) is an effective anticancer drug. It has been shown that a short-term exercise performed prior to DOX-treatment has no effect on cardiotoxicity in young rats. In the present study, old and young rats were evaluated to determine the protective effects of pre-treatment with short-term exercise on DOX-induced oxidative damage in cardiac tissue.Methods: Forty-eight male Wistar rats were randomly divided into two groups of young and old, and later divided into three sub-groups of young+DOX, young+training+DOX, young+training+salin, old+DOX, old+training+DOX and old+training+salin. The training protocol included treadmill running for 25-39 min/day at 15-17 m/min, 5 days/week for three weeks. All treatments were carried out 24h after the last exercise bout. The rats were sacrificed 48h after DOX administration.Results: Although DOX injection significantly affected the cardiac tissue of old rats compared to young rats, pretreatment with endurance training in DOX-treated rats caused an increase in Heat shock protein (3.02% vs. 23.36) and superoxide dismutase (30.12% vs. 31.12), and a decrease in malondialdehyde (10.92% vs. 19.60) in both old and young rats.Conclusion: Although DOX-induced production of free radicals and cardiotoxicity in aged rats is more than that in young rats, the short-term aerobic exercise reduced the damaging effects of free radicals in the old rats more than in young ones. The concentration of antioxidant enzymes also increases with exercise in the old rats compared to young rats.

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Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress

Cited by 86 publications

References 55 publications

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review

Age-Related Changes in Doxorubicin-Induced Oxidative Damage: Protective and Pretreatment Effects of Short-Term Aerobic Exercise

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