Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy

Catanzaro, Michael P.; Weiner, Ashley A.; Kaminaris, Amanda; Li, Cairong; Cai, Fei; Zhao, Fengyi; Kobayashi, Satoru; Kobayashi, Tamayo; Huang, Yuan; Sesaki, Hiromi; Liang, Qiangrong

doi:10.1096/fj.201802663r

Cited by 136 publications

(124 citation statements)

References 47 publications

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“…As a starting point, initial proof-of-concept experiments were undertaken in rat H9c2 cardiomyocytes 20 , a low-cost, tractable model used most typically in toxicology research and early-stage cardiac drug discovery. Notably, this body of work includes more than 300 studies of anthracycline toxicity [21][22][23][24][25][26][27][28][29][30][31][32][33][34] as well as high-throughput, phenotypedriven screens for novel cardioprotective agents 35,36 . Viability as measured by the CellTiter-Glo ATP generation assay was markedly impaired by DOX, with half-maximal effects at 150-250 nM at 24 and 48 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the widely reported utility of H9c2 cells [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] , their applicability as a predictive model in cardiac drug development is compromised by their continuous proliferation, lack of the sodium/calcium exchanger NCX1, lack of beating, and skeletal muscle potential 20,38,39 . Moreover, explicit disparities have been reported in drug effects relating to cardioprotection and cardiotoxicity in this model, compared with human cells 40,41 .…”

Section: Inhibitors Of Map4k4 Confer Protection From Dox In Human Pscmentioning

confidence: 99%

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Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death. With earlier diagnosis and improved treatments for cancer, cardiovascular disease has become the main alternative cause of death in cancer survivors 1-4. This heightened risk is ascribable to the cardiac toxicity of several routine anti-cancer agents including, especially, anthracyclines like doxorubicin (DOX) 5. Though some relief can result from standard heart failure medications, no approved therapy apart from the iron chelator dexrazoxane addresses the responsible cytotoxic mechanisms and effector pathways operating in the damaged cardiomyocytes. For anthracyclines, these include diverse reported mediators-binding to nuclear topoisomerase 2β, thereby triggering DNA double-strand breaks, p53-dependent apoptosis, mitochondrial dysfunction, reactive oxygen species, and programmed iron-dependent cell death (ferroptosis) 1,6,7. Cardiotoxicity can be acute, early, or late; early intervention based on subclinical abnormalities may be key to averting the delayed or cumulative effects 8. Notably, acute toxicity is seen in up to 30% of patients receiving anthracyclines, soon after infusion 4. Current cardioprotection trials in cancer rely chiefly on routine heart failure medications (ACE inhibitors, β-blockers, angiotensin receptor blockers), which mitigate the symptoms and signs, with little or no demonstrated impact on cardiomyocyte death. Therapeutic progress has been hampered, in part, by the failure of animal models alone to predict clinical success in cardioprotection. For instance, nearly all strategies for protection in ischemic heart disease, a more intensively studied indication, have failed between phases I and I...

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Section: Resultsmentioning

confidence: 99%

Section: Inhibitors Of Map4k4 Confer Protection From Dox In Human Pscmentioning

confidence: 99%

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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“…Previous analysis showed little changes in Drp1 and more mitochondrial elongation in doxorubicin-treated hearts (Abdullah et al, 2019). It was also suggested that levels of Drp1 and Drp1 Ser 616 phosphorylation were increased following doxorubicin challenge (Xia et al, 2017;Catanzaro et al, 2019). Indeed, these authors went on to reveal elevated mitochondrial autophagy, contributing to mitochondrial dysfunction and doxorubicin toxicity.…”

Section: Discussionmentioning

confidence: 96%

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

Sun

et al. 2020

Front. Physiol.

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Doxorubicin is a valuable antineoplastic drug although its clinical use is greatly hindered by its severe cardiotoxicity with dismal target therapy available. Luteolin is a natural product extracted from vegetables and fruits with a wide range of biological efficacies including anti-oxidative, anti-tumorigenic, and anti-inflammatory properties. This study was designed to examine the possible effect of luteolin on doxorubicin-induced cardiotoxicity, if any, and the mechanism(s) involved with a focus on mitochondrial autophagy. Luteolin application (10 µM) in adult mouse cardiomyocytes overtly improved doxorubicin-induced cardiomyocyte contractile dysfunction including elevated peak shortening amplitude and maximal velocity of shortening/relengthening along with unchanged duration of shortening and relengthening. Luteolin alleviated doxorubicininduced cardiotoxicity including apoptosis, accumulation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Furthermore, luteolin attenuated doxorubicin-induced cardiotoxicity through promoting mitochondrial autophagy in association with facilitating phosphorylation of Drp1 at Ser 616 , and upregulating TFEB expression. In addition, luteolin treatment partially attenuated low dose doxorubicininduced elongation of mitochondria. Treatment of Mdivi-1, a Drp1 GTPase inhibitor, negated the protective effect of luteolin on levels of TFEB, LAMP1, and LC3B, as well as loss of mitochondrial membrane potential and cardiomyocyte contractile dysfunction in the face of doxorubicin challenge. Taken together, these findings provide novel insights for the therapeutic efficacy of luteolin against doxorubicin-induced cardiotoxicity possibly through improved mitochondrial autophagy.

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“…Pinocembrins’ cardioprotective potential is further endorsed by its vasorelaxant ( Estrada et al., 2020 ) effects which could aid in the preservation of cardiac function by alleviating cardiac fibrosis and left ventricular dysfunction ( Rasul et al., 2013 ; Borriello et al., 2019 ), which is a hallmark for Dox-induced cardiotoxicity. Literature suggests that H9c2 cells are a suitable model to study the effects of Dox-induced cardiotoxicity in an in vitro setting, as it has been shown that the major adverse effects reported in patients exposed to Doxcan be induced in these cells ( Catanzaro et al., 2019 ; Dallons et al., 2020 ; Faridvand et al., 2020 ; Hu et al., 2020 ). Hence, the objective of the current study was to i) assess the prophylactic effect of Pin against the cardiotoxicity inferred by Dox administration using an H9c2 cardiomyoblast model, as well as ii) to evaluate the effect of Pin on the chemotherapeutic potential of Dox in an MCF-7 breast cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

et al. 2020

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Background The clinical use of Doxorubicin (Dox) is significantly limited by its dose-dependent cardiotoxic side effect. Accumulative evidence suggests that the use of flavonoids, such as the antioxidative Pinocembrin (Pin), could be effective in the prevention of Dox-induced cardiotoxicity. Accordingly, we investigated the ability of pinocembrin (Pin) to attenuate Dox-induced cardiotoxicity in an in vitro H9c2 cardiomyoblast model. Methodology The cardioprotective potential of Pin was established in H9c2 cells. Here, cells were treated with Dox (2μM), Dox (2μM) + Pin (1μM), and Dox (2μM) + Dexrazoxane (20μM) for 6 days. Thereafter, the safe co-administration of Pin with Dox, in a cancer environment, was investigated in MCF-7 breast cancer cells subjected to the same experimental conditions. Untreated cells served as the control. Subsequently, Pin’s ability to attenuate Dox-mediated oxidative stress, impaired mitochondrial bioenergetics and potential, as well as aggravated apoptosis was quantified using biochemical assays. Results The results demonstrated that co-treatment with Pin mitigates Dox-induced oxidative stress by alleviating the antioxidant enzyme activity of the H9c2 cells. Pin further reduced the rate of apoptosis and necrosis inferred by Dox by improving mitochondrial bioenergetics. Interestingly, Pin did not decrease the efficacy of Dox but, rather increased the rate of apoptosis and necrosis in Dox-treated MCF-7 cells. Conclusion The findings presented in this study showed, for the first time, that Pin attenuates Dox-induced cardiotoxicity without reducing its chemotherapeutic effect. We propose that additional studies, using in vivo models, should be conducted to further investigate Pin as a suitable candidate in the prevention of the cardiovascular dysfunction inferred by Dox administration.

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Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy

Cited by 136 publications

References 47 publications

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

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