Cardiomyocyte apoptosis vs autophagy with prolonged doxorubicin treatment: comparison with osteosarcoma cells

Tacar, Oktay; Indumathy, Sivanjah; Tan, Mei Lin; Baindur-Hudson, Swati; Friedhuber, Anna; Dass, Crispin R.

doi:10.1111/jphp.12324

Cited by 13 publications

(13 citation statements)

References 39 publications

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“…The interplay between protective autophagocytic processes and apoptosis was also suggested to be a regulator of DOX-inducted injury [13,78], potentially allowing the alleviation of metabolic stress after MOMP or after other ROS-induced impairment of mitochondria [72].…”

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

confidence: 99%

“…Indeed, upregulation of the major autophagy inducer Beclin-1 has been observed in cardiomyocytes in a time and dose dependent manner after DOX exposure [78]. Importantly, as Beclin-1 is a substrate of caspase-3, the down-regulation of caspase-3 activity in differentiated cardiomyocytes may guarantee execution of autophagy, therefore alleviating cellular metabolic injury.…”

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

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

confidence: 99%

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

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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show abstract

“…Doxorubicin (DOX) is an effective anthracycline antitumor antibiotic and is extensively used for treatment of numerous types of malignant tumors, including osteosarcoma, breast carcinoma and lung cancer (1)(2)(3). However, because of cumulative and dose-dependent cardiotoxicity, the clinical application of DOX is limited.…”

Section: Introductionmentioning

confidence: 99%

Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating microRNA-1 expression

Tang

Li³

et al. 2016

Experimental and Therapeutic Medicine

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Doxorubicin (DOX) is an effective anthracycline anti-tumor antibiotic. Because of its cardiotoxicity, the clinical application of DOX is limited. Paeoniflorin (PEF), a monoterpene glucoside extracted from the dry root of Paeonia, is reported to exert multiple beneficial effects on the cardiovascular system. The present study was designed to explore the protective effect of PEF against DOX-induced cardiomyocyte apoptosis and the underlying mechanism. In cultured H9c2 cells, PEF (100 µmol/l) was added for 2 h prior to exposure to DOX (5 µmol/l) for 24 h. Cell viability, creatine kinase activity, cardiomyocyte apoptosis, intracellular reactive oxygen species (ROS) levels, and the expression of microRNA-1 (miR-1) and B-cell lymphoma 2 (Bcl-2) were measured following treatment with PEF and/or DOX. The results showed that treatment with DOX notably induced cardiomyocyte apoptosis, concomitantly with enhanced ROS generation, upregulated miR-1 expression and downregulated Bcl-2 expression. These effects of DOX were significantly inhibited by pretreatment of the cells with PEF. These results suggest that the inhibitory effect of PEF on DOX-induced cardiomyocyte apoptosis may be associated with downregulation of miR-1 expression via a reduction in ROS generation.

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“…Although oxidative stress plays a major role in the pathogenesis of Dox-induced cardiotoxicity, Dox-induced inflammatory effects on the myocardium and the vasculature are mediated through the upregulation of NF- κ B expression [ 30 ]. Furthermore, there is accumulated evidence to suggest that mechanisms of programmed cell death, such as apoptosis which is characterized by nuclear and chromosomal DNA fragmentation, cell shrinkage, and blebbing as well as autophagy, also play an important role in the pathogenesis of cardiotoxicity [ 30 , 31 ]. Therefore, assessment of markers for cardiac damage, oxidative stress, inflammation, apoptosis, and DNA fragmentation is important in the diagnosis of anthracycline-induced cardiotoxicity as well as in the determination of mechanism of action of therapeutic interventions used against them.…”

Section: Discussionmentioning

confidence: 99%

Nauclea orientalis (L.) Bark Extract Protects Rat Cardiomyocytes from Doxorubicin-Induced Oxidative Stress, Inflammation, Apoptosis, and DNA Fragmentation

Sandamali

Hewawasam

Jayatilaka

et al. 2022

Oxidative Medicine and Cellular Longevity

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The therapeutic efficacy of anthracycline antibiotic, doxorubicin (Dox), is hampered due to the dose-dependent cardiotoxicity. The objective of the study was to explore the counteraction of aqueous bark extract of Nauclea orientalis in Dox-induced cardiotoxicity in Wistar rats. The acute and subchronic toxicity study performed with 2.0 g/kg of the plant extract revealed biochemical and haematological parameters to be within the physiological range, and no histological alterations were observed in any organs isolated. Screening of plant extract for the protection of the myocardium from Dox-induced oxidative stress, inflammation, and apoptosis was performed on five groups of rats: control, plant extract control, Dox control (distilled water (D.H2O) 2 weeks + on the 11th day single injection of Dox, 18 mg/kg), plant + Dox (2.0 g/kg plant extract 2 weeks + on the 11th day Dox, 18 mg/kg), and positive control, dexrazoxane. A significant increase in cardiac biomarkers and lipid peroxidation ( p < 0.001 ) and a significant decrease in antioxidant parameters ( p < 0.001 ) were observed in the Dox control group. All these parameters were reversed significantly ( p < 0.05 ) in the plant-pretreated group. The histopathological assessment of myocardial damage provided supportive evidence for the biochemical results obtained. Inflammatory markers, myeloperoxidase, expression of TNFα and caspase-3, and DNA fragmentation (TUNEL positive nuclei) were significantly elevated ( p < 0.05 ), and expression of Bcl-2 was significantly decreased ( p < 0.05 ) in the Dox control; however, all these parameters were significantly reversed in the plant extract-treated group. In conclusion, the aqueous bark extract of Nauclea orientalis (2.0 g/kg) has the ability to attenuate the Dox-induced oxidative stress, inflammation, apoptosis, and DNA fragmentation in Wistar rats.

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Cardiomyocyte apoptosis vs autophagy with prolonged doxorubicin treatment: comparison with osteosarcoma cells

Abstract: In culture, cells of both cardiomyocytes and OS revealed a predominant pro-apoptotic response at the expense of autophagy, although both seemed to be occurring in vivo.

Cited by 13 publications

References 39 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating microRNA-1 expression

Nauclea orientalis (L.) Bark Extract Protects Rat Cardiomyocytes from Doxorubicin-Induced Oxidative Stress, Inflammation, Apoptosis, and DNA Fragmentation

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