Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress

Gratia, Séverine; Kay, Laurence; Potenza, Lucia; Seffouh, Amal; Novel-Chate, Valérie; Schnebelen, Coralie; Sestili, Piero; Schlattner, Uwe; Tokarska‐Schlattner, Malgorzata

doi:10.1093/cvr/cvs134

Cited by 105 publications

(99 citation statements)

References 53 publications

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“…DOX affects the mTOR pathway through AMPK, Akt, and p53-dependent and -independent mechanisms (11,37). Moreover, the induction of physiological hypertrophy with exercise is mediated through IGF-I, Akt, and mTOR signaling (26).…”

Section: Sed+dox Ex+dox Ex Dox (-) (+) (-) (+) (-) (+) (-) (+) (-) (+mentioning

confidence: 99%

“…Although exercise training has previously been shown to increase Akt phosphorylation (3), the role of Akt in DOX cardiotoxicity is less clear. While some studies have shown DOX decreases Akt phosphorylation, others have observed elevated Akt activity in vivo (6,11,25). Because many factors influence Akt phosphorylation, it appears the experimental model is very important for interpretation of Akt activity.…”

Section: Sed+dox Ex+dox Ex Dox (-) (+) (-) (+) (-) (+) (-) (+) (-) (+mentioning

confidence: 99%

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Concomitant low-dose doxorubicin treatment and exercise

Sturgeon

Schadler

Muthukumaran

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 ϫ 10 5 ) were injected subcutaneously into the scruff of 6-to 8-wk-old male C57BL/6 mice (n ϭ 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/ wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) ϩ vehicle, 2) SED ϩ DOX, 3) EX ϩ vehicle, and 4) EX ϩ DOX. Tumor volume was attenuated in DOX and lowest in EX ϩ DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ␤-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOXinduced cardiotoxicity in a murine model of melanoma. neoplasm; drug therapy; cardiotoxicity; heart DOXORUBICIN (DOX) is an anthracycline with broad clinical application across the cancer spectrum as an effective antineoplastic agent (14, 30). However, progressive and dose-dependent early and late-onset cardiotoxicity limits the clinical efficacy of DOX (9). Acute cardiotoxicity is associated with arrhythmias and transient left ventricular (LV) dysfunction, whereas late-onset cardiomyopathy, which can occur up to 15 years after DOX administration, can manifest with overt LV dysfunction and heart failure (35). This is a significant clinical issue given cancer survivors already face a 15-fold increased rate of heart failure (27).There are numerous transcriptional and posttranslational pathophysiological mechanisms associated with DOX-induced cardiotoxicity, including increased generation of reactive oxygen species and lipid peroxidation, mitochondrial damage, DNA damage, reduction in protein synthesis, increased apoptosis, and alterations in ␤-adrenergic signaling and Ca 2ϩ handling (28). A recent study also showed that DOX caused nearly full extinction of competent cardiac progenitor cells. Subsequent intramyocardial injections of syngeneic cardiac progenitors rescued the heart from DOX-induced cardiotoxicity (7). These data suggest that a reduction in cardiomyocyte cell number...

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Section: Sed+dox Ex+dox Ex Dox (-) (+) (-) (+) (-) (+) (-) (+) (-) (+mentioning

confidence: 99%

Section: Sed+dox Ex+dox Ex Dox (-) (+) (-) (+) (-) (+) (-) (+) (-) (+mentioning

confidence: 99%

Concomitant low-dose doxorubicin treatment and exercise

Sturgeon

Schadler

Muthukumaran

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…10,11 Interestingly, mitochondrial alterations also seem to be involved in doxorubicin-mediated cardiotoxicity. 12,13 Moreover, alterations in energy signaling pathways, such as the AMP-activated protein kinase (AMPK), have been recently shown to be involved in doxorubicin cardiotoxicity, 12 but possible sex differences have not yet been evaluated.…”

mentioning

confidence: 99%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

114

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Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

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“…4 The inhibition of this signalling pathway causes cellular energy deficits. 5 Metformin on the other hand is currently one of the drugs used worldwide to treat diabetes mellitus type 2. It is known to be an insulin sensitizer and has a low potential to produce adverse effects especially in patients with underlying cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

Effect of metformin on ECG, HR and BP of rats administered with cardiotoxic agent doxorubicin

Emeka

AlAhmed

2017

Int J Basic Clin Pharmacol

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Background: Cardiovascular complications during drug therapy is worrisome and has been known to increase morbidity and mortality. The aim of this study was to investigate the effect of metformin on BP, HR, and ECG, after subacute administration of doxorubicin in rats.Methods: Laboratory acclimatised animals were divided into 4 experimental groups consisting of group I as the control, given 0.5ml normal saline. Group II, received 3mg/kg doxorubicin on alternate days, while group III was given 300mg/kg metformin. The last group of animals were treated with 300mg/kg metformin, 30 min later, the animals were injected doxorubicin ip. The treatment lasted for 15 days thereafter, ECG, HR and BP were measured with anaesthesia.Results: Result showed that doxorubicin induced ECG changes in terms of increased PR and QT intervals significantly. Whereas, QRS and RR intervals were at same time significantly decreased. Metformin was observed to significantly attenuate these changes. In addition, metformin restored decreases in HR that was caused by doxorubicin in a significant fashion. However, metformin alone produced a decrease in HR compared with control. The observed reduced SBP and DBP produced by doxorubicin were also alleviated by the administration of metformin. There were increases in BP parameters measured in normotensive rats with metformin alone.Conclusions: In conclusion, metformin was found to attenuate doxorubicin-induced alteration in ECG pattern and restored the mechanical and physiological functions of the rat heart. Our data further suggests monitoring of CVS changes such as ECG particularly with drugs known to cause myocardial injury.

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Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress

Cited by 105 publications

References 53 publications

Concomitant low-dose doxorubicin treatment and exercise

Concomitant low-dose doxorubicin treatment and exercise

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Effect of metformin on ECG, HR and BP of rats administered with cardiotoxic agent doxorubicin

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