Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies

Octavia, Yanti; Tocchetti, Carlo G.; Gabrielson, Kathleen L.; Janssens, Stefan; Crijns, Harry J.G.M.; Moens, An L.

doi:10.1016/j.yjmcc.2012.03.006

Cited by 1,173 publications

(986 citation statements)

References 148 publications

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“…75 The transcriptional activation of NF-κB and COX-II by DOX increases oxidative stress and their transcriptional suppression by naringin has been may have also reduced the DOX-induced oxidative stress. [76][77][78][79] Nrf2 is an important transcriptional factor responsible for the expression of different antioxidant genes and its suppression by DOX may have rested in the increased oxidative causing a decline in all the antioxidants. The presence of naringin may have triggered the activation Nrf2 signalling pathway reducing the DOX induced oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Ch¹,

Jagetia²,

Lalrinengi³

2017

MOJAP

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Doxorubicin a photosensitive antibiotic is frequently used to treat various malignancies in clinics; however, doxorubicin is also taken up by the normal cells of the body leading to increased oxidative stress and subsequently DNA damage and dysfunction in the cells. The agents which can reduce the adverse effect of doxorubicin will of great value. The present study has attempted to study the effect of naringin a citrus flavonoid on the doxorubicininduced oxidative stress in mice liver. The mice were administered with 0, 1, 5 or 10mg/ kg body weight of doxorubicin and treated with 10mg/kg body weight of naringin before or after doxorubicin treatment. The glutathione concentration and lipid peroxidation and activities of glutathione-s-transferase, catalase and super oxide dismutase were studied at 0.5, 1, 2 and 4h post-treatment in the mouse liver. The doxorubicin increased the lipid peroxidation in a dose dependent manner at all the post treatment times. Conversely, it attenuated the activities of glutathione-s-transferase, catalase and super oxide dismutase in dose dependent fashion and time dependent manner. A similar effect was observed for glutathione concentration. Treatment of mice with naringin before or after doxorubicin treatment elevated all the antioxidants and reduced the doxorubicin -induced lipid peroxidation. The effect of naringin pretreatment was more effective when compared to its post treatment. The naringin was very effective in reducing the oxidative stress induced by doxorubicin as indicated by the elevated levels of glutathione concentration, glutathiones-transferase, catalase and super oxide dismutase. The pretreatment of naringin was better than its post treatment.

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Section: Discussionmentioning

confidence: 99%

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Ch¹,

Jagetia²,

Lalrinengi³

2017

MOJAP

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“…Apoptosis may contribute to DOX-induced DCM and heart failure [12,[15][16][17] either by acute apoptotic damage of cardiomyocytes or by mechanisms that increase their future apoptosis likelihood. However, the relevance of apoptosis in DOX-induced dilated cardiomyopathy is often questioned as the amount of apoptosis in biopsies from patients or from heart transplants following DCM is low compared to necrotic cell death [18].…”

Section: Evidence For Cardiomyocyte Apoptosis In Dox-induced Dcmmentioning

confidence: 99%

“…Nevertheless, apoptosis has also been implicated in most of the concurring models of DOX-induced DCM. To this end, increased production of ROS is considered to be a major inducer of cardiac malignancy following DOX [12]. ROS is usually thought to be elevated in cardiomyocyte by DOX binding to cardiolipin at the inner mitochondrial membrane, impairing mitochondrial respiration [72].…”

Section: The Apoptosis Hypothesis Relevant To Other Pathways In Dox-imentioning

confidence: 99%

“…Besides this direct impairment of cardiac function, ROS-induced oxidative stress can also induce cardiomyocyte apoptosis [75]. Thereby, oxidative stress has been shown to transcriptionally alter BCL-2 family protein expression, leading to MOMP and cytochrome-c release [12,76].…”

Section: The Apoptosis Hypothesis Relevant To Other Pathways In Dox-imentioning

confidence: 99%

“…Therefore, to understand and mitigate DOX induced chronic DCM, several excellent reviews have focused on the effect of DOXderegulated oxidative metabolism [11,12], DOX-induced autophagy [13], or on the broader clinical scope of DOX-induced DCM [14]. We here focus on the role of apoptosis to discuss potential molecular underpinnings of a chronic DCM phenotype, paying specific attention on apoptosis alteration after cardiomyocyte differentiation and DOX exposure.…”

Section: Introductionmentioning

confidence: 99%

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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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MitoChip

Desai¹,

Jenkins²

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies

Cited by 1,173 publications

References 148 publications

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Treatment of Mice with Naringin Alleviates the Doxorubicin-Induced Oxidative Stress in the Liver of Swiss Albino Mice

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

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