Mitochondrial dynamics imbalance and mitochondrial dysfunction contribute to the molecular cardiotoxic effects of lenvatinib

Akyıldız, Ayşenur Günaydın; Boran, Tuğçe; Jannuzzi, Ayşe Tarbın; Alpertunga, Büket

doi:10.1016/j.taap.2021.115577

Cited by 12 publications

(6 citation statements)

References 72 publications

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“…In experiments on human aortic endothelial cells, HN treatment protects from OS via downregulation of NOX2 (Superoxide-Generating NADPH Oxidase Heavy Chain Subunit) and TxNIP (Thioredoxin Interacting Protein) gene expression and leads to a reduction in ROS and protein carbonyl [65]. NOX2 is the main player in cardiac oxidative damage [78], while TxNIP and protein carbonyl are markers of metabolic and oxidative stress [79,80]. Similarly, protective properties against oxidative stress were shown for HN analogue HNG on SH-SY5Y neuroblastoma cells, where HNG acted via the PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B) pathway [81], a crucial signalling pathway involved in the regulation of apoptosis, cell differentiation and proliferation [82].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

Dabravolski

Nikiforov

Стародубова

et al. 2021

IJMS

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Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.

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Section: Mechanisms Of Actionmentioning

confidence: 99%

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

Dabravolski

Nikiforov

Стародубова

et al. 2021

IJMS

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“…Recent studies have suggested mitochondrial membrane potential (MMP) imbalance and ROS accumulation contributes to the toxicity of Lenvatinib [ 54 ]. The MMP of ZLF-095 and Lenvatinib treated cells were detected after 48 h treatment by flow cytometry after staining with rhodamine 123 (Rh123).…”

Section: Resultsmentioning

confidence: 99%

A novel VEGFR inhibitor ZLF-095 with potent antitumor activity and low toxicity

Wang

et al. 2023

Heliyon

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“…Lenvatinib is a small molecule tyrosine kinase inhibitor and clinically used for the treatment of radio‐iodide refractory differentiated thyroid cancer and other cancers. Related clinical reports suggested that lenvatinib had a serious risk of hypertension and cardiotoxicity, with mitochondrial toxicity in H9c2 cardiomyoblastic cell line exposed to lenvatinib 18–21 . With the increasing clinical use of lenvatinib, the effects of the parent and its metabolites discharged into the water on non‐target organisms should be taken into account.…”

Section: Discussionmentioning

confidence: 99%

Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated‐oxidative stress generation

Liu

Huang

Wan

et al. 2022

Environmental Toxicology

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Due to an increasing number of abused drugs dumped into the wastewater, more and more drugs are detected in the water environment, which may affect the survival of aquatic organisms. Lenvatinib is a multi-targeted tyrosine kinase inhibitor, and is clinically used to treat differentiated thyroid cancer, renal epithelial cell carcinoma and liver cancer. However, there are few reports on the effects of lenvatinib in embryos development. In this study, zebrafish embryos were used to evaluate the effect of lenvatinib on cardiovascular development. Well-developed zebrafish embryos were selected at 6 h post fertilization (hpf) and exposed to 0.05 mg/L, 0.1 mg/L and 0.2 mg/L lenvatinib up to 72 hpf. The processed embryos demonstrated cardiac edema, decreased heart rate, prolonged SV-BA distance, inhibited angiogenesis, and blocked blood circulation. Lenvatinib caused cardiac defects in the whole stage of cardiac development and increased the apoptosis of cardiomyocyte.Oxidative stress in the processed embryos was accumulated and inhibiting oxidative stress could rescue cardiac defects induced by lenvatinib. Additionally, we found that lenvatinib downregulated Notch signaling, and the activation of Notch signaling could rescue cardiac developmental defects and downregulate oxidative stress level induced by lenvatinib. Our results suggested that lenvatinib might induce cardiac developmental toxicity through inducing Notch mediated-oxidative stress generation, raising concerns about the harm of exposure to lenvatinib in aquatic organisms.

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Mitochondrial dynamics imbalance and mitochondrial dysfunction contribute to the molecular cardiotoxic effects of lenvatinib

Cited by 12 publications

References 72 publications

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

A novel VEGFR inhibitor ZLF-095 with potent antitumor activity and low toxicity

Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated‐oxidative stress generation

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