Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib

Bouitbir, Jamal; Alshaikhali, Abdallah; Panajatovic, Miljenko V.; Abegg, Vanessa Fabienne; Paech, Franziska; Krähenbühl, Stephan

doi:10.1016/j.tox.2019.152281

Cited by 42 publications

(31 citation statements)

References 53 publications

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“…who showed that imatinib enhanced the cleavage of caspase 3/7 in C2C12 myotubes exposed for 24 h ( Damaraju et al., 2018 ). We have shown previously the relationship between mitochondrial superoxide accumulation and sunitinib-associated toxicity in cardiac H9c2 cells by co-incubation with the mitochondria-specific ROS scavenger mito-TEMPO ( Bouitbir et al., 2019 ). If mitochondrial accumulation of superoxide is the driving force for myotoxicity of imatinib and dasatinib, we could expect similar results by mito-TEMPO regarding the toxicity of these compounds on C2C12 cells.…”

Section: Discussionmentioning

confidence: 95%

“…Previously, we and others have shown that mitochondrial dysfunction plays a pivotal role in TKI-associated myocardial and liver toxicity ( Kerkela et al., 2006 ; Will et al., 2008 ; Mingard et al., 2018 ; Bouitbir et al., 2019 ). In the current study, the cellular ATP content was affected at clearly lower concentrations than membrane toxicity for both imatinib and dasatinib, suggesting mitochondrial toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…To elucidate the toxic effects of the three investigated TKIs, we first assessed the plasma membrane integrity and the intracellular ATP content in myoblasts and myotubes exposed to different concentrations (Bouitbir et al, 2019). After exposure of C2C12 myoblasts and myotubes for 24 h, imatinib was slightly membrane toxic and depleted the ATP content in a concentration-dependent fashion ( Figures 1A, B).…”

Section: Membrane Toxicity and Intracellular Atp Content In C2c12 Myomentioning

confidence: 99%

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Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells

et al. 2020

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Membrane Toxicity and Intracellular Atp Content In C2c12 Myomentioning

confidence: 99%

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Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells

et al. 2020

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“…Clinical research observed aberrantly shaped, swollen mitochondria in cardiomyocytes of patients who developed congestive heart after sunitinib treatment (Chu et al, 2007). Bouitbir et al (2019) demonstrated that the oxidative stress caused by sunitinib was mainly responsible for the mitochondrial damage and final apoptosis of cardiomyocytes. By suppressing mitochondrial electron transport chain enzyme complexes, sunitinib induced ROS accumulation, which further decreased MMP and destroyed the mitochondrial structure to initiate caspases cascade reactions.…”

Section: Trastuzumabmentioning

confidence: 99%

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Wei

Zhang

et al. 2020

Front. Cell Dev. Biol.

108

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Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

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“…9 Bouitbir et al showed that sunitinib increases the accumulation of mitochondrial reactive oxygen species (ROS) and reduces cellular ATP and reduced glutathione (GSH) stores. 10 A decrease in these high-energy phosphate concentrations has been documented to result in oxidative stress and membrane lipid peroxidation (LPO). 11 As is known, an increase in ROS production changes the balance between oxidant and antioxidant in favor of oxidants, causing oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of adenosine triphosphate against sunitinib-related skin damage in rats

et al. 2020

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Cutaneous side effects associated with sunitinib use are a major problem in patients receiving cancer treatment. The aim of this study was to investigate the protective effect of adenosine triphosphate (ATP) against possible skin damage resulting from sunitinib use in rats. Thirty Albino Winstar rats were divided into the following three groups: healthy controls (HCs, n = 10), sunitinib (SUN, n = 10), and sunitinib + ATP (SAT, n = 10). ATP was injected intraperitoneally at a dose of 2 mg/kg. One hour subsequent to the administration of ATP and 0.9% NaCl, the SAT and SUN groups were orally administered a dose of 25 mg/kg sunitinib to the stomach. Macroscopic evaluation of the skin indicated lower levels of skin damage in the SAT group than in the SUN group. As an indicator of oxidative stress, malondialdehyde (MDA), total oxidant status (TOS), and oxidative stress index (OSI) levels were significantly higher in the SUN group than in the HC group, while total glutathione (tGSH) and total antioxidant status (TAS) levels were significantly lower. However, MDA, TOS, and OSI levels were significantly lower in the SAT group than in the SUN group, while tGSH and TAS levels were significantly higher. Histopathological examination revealed keratin plugs with edema, vasopathology, and inflammatory cell infiltration in the SUN group. The SAT group showed less necrotic epithelium, keratin plugs, edema, and vasopathology than the SUN group. ATP can be effective in preventing skin damage caused by sunitinib use by reducing oxidative stress.

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Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib

Cited by 42 publications

References 53 publications

Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells

Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Protective effect of adenosine triphosphate against sunitinib-related skin damage in rats

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