Mechanisms of Cardiotoxicity Associated with Tyrosine Kinase Inhibitors in H9c2 Cells and Mice

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

doi:10.15420/ecr.2020.15.1.po10

Cited by 3 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…H9c2 cardiomyoblasts have been used for mitochondrial toxicity assessment of DOX, and demonstrated increased mitochondrial swelling [ 278 ], mtROS [ 279 ], mitochondrial fission [ 280 ], decreased MMP [ 281 ], and OCR and ATP production [ 282 ], whereas trastuzumab led to increased mtROS and decreased MMP [ 185 ]. Treatment of H9c2 cells with tyrosine kinase inhibitors, such as imatinib, sorafenib, and sunitinib, resulted in mitochondrial swelling, cristae loss, MMP reduction, inhibition of MRC complexes, superoxide accumulation, and cellular GSH depletion [ 283 , 284 , 285 ]. Similar mitochondrial impairments were also observed with other toxicants, such as As 2 O 3 [ 286 ] and simvastatin [ 151 ].…”

Section: Limitations Of Current Preclinical Models For Assessing Card...mentioning

confidence: 99%

“…Cardiac spheroids are a type of self-assembled ball shape structure comprising one or multiple cell types. They have been used to verify the cardiotoxicity of DOX, sunitinib, verapamil, and quinidine at clinically relevant concentrations, assessed by cell viability, contractility, MMP, and endoplasmic reticulum integrity [ 283 , 317 , 318 ]. Currently, cardiac spheroids can be easily generated in microscale platforms, such as 96/384-well plates [ 300 , 330 ], to decrease the number of cardiac cells.…”

Section: Limitations Of Current Preclinical Models For Assessing Card...mentioning

confidence: 99%

“…On the contrary, when grown under conditions of low-glucose or glucose-free media with abundant oxygen supply, cardiomyocytes are forced to use OXPHOS for ATP production [ 340 ], exhibiting mitochondrial respiration comparable to in vivo conditions [ 341 ]. Cardiomyocytes, including H9c2 [ 283 , 284 , 285 , 342 ], hESC-CMs [ 140 ], and hiPSC-CMs [ 343 ], grown in galactose become susceptible to mitochondrial toxicants [ 344 , 345 ]. None of the H9c2 cells cultured in galactose survived troglitazone treatment, whereas those in high-glucose medium were unaffected 24 h post-treatment [ 346 ].…”

Section: Proposed Preclinical Model Of Cardiomyocytes For Assessment ...mentioning

confidence: 99%

See 2 more Smart Citations

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Tang

Wang

et al. 2022

Pharmaceutics

View full text Add to dashboard Cite

Drug-induced cardiotoxicity not only leads to the attrition of drugs during development, but also contributes to the high morbidity and mortality rates of cardiovascular diseases. Comprehensive testing for proarrhythmic risks of drugs has been applied in preclinical cardiac safety assessment for over 15 years. However, other mechanisms of cardiac toxicity have not received such attention. Of them, mitochondrial impairment is a common form of cardiotoxicity and is known to account for over half of cardiovascular adverse-event-related black box warnings imposed by the U.S. Food and Drug Administration. Although it has been studied in great depth, mitochondrial toxicity assessment has not yet been incorporated into routine safety tests for cardiotoxicity at the preclinical stage. This review discusses the main characteristics of mitochondria in cardiomyocytes, drug-induced mitochondrial toxicities, and high-throughput screening strategies for cardiomyocytes, as well as their proposed integration into preclinical safety pharmacology. We emphasize the advantages of using adult human primary cardiomyocytes for the evaluation of mitochondrial morphology and function, and the need for a novel cardiac safety testing platform integrating mitochondrial toxicity and proarrhythmic risk assessments in cardiac safety evaluation.

show abstract

Section: Limitations Of Current Preclinical Models For Assessing Card...mentioning

confidence: 99%

Section: Limitations Of Current Preclinical Models For Assessing Card...mentioning

confidence: 99%

Section: Proposed Preclinical Model Of Cardiomyocytes For Assessment ...mentioning

confidence: 99%

See 1 more Smart Citation

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Tang

Wang

et al. 2022

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…In the event of hypoxia, it can not only lead to heart failure after traumas, but also injure multiple organs resulting in multi-organ dysfunction (1). Various studies have been conducted so far focusing molecular regulators in myocardial cells (2). Hypoxia models are adopted in myocardial infarction research and are often used in evaluating the effects of active substances on cellular morphology and functions (3).…”

Section: Introductionmentioning

confidence: 99%

The interplay between HIF-1α and long noncoding GAS5 regulates the JAK1/STAT3 signalling pathway in hypoxia-induced injury in myocardial cells

Li¹,

Song²,

Liu³

et al. 2021

Cardiovasc Diagn Ther

View full text Add to dashboard Cite

Background: Long non-coding RNA (lncRNA) GAS5 is associated with hypoxia-induced diseases whereas hypoxia-inducible factor-1α (HIF-1α) plays an important role in hypoxic injury of cells. The current study explores the regulatory functions of GAS5/HIF-1α which co-play in anoxic injury among rat cardiomyocytes H9C2 cells.Methods: Hypoxia in vitro model was established through anoxic incubation while normal culture of H9C2 cells was considered as control. The expression levels of GAS5 and HIF-1α were quantified through RT-qPCR. CCK-8 was applied to determine cell viability. Cell apoptosis rate was calculated using flow cytometry whereas inflammatory cytokines were detected using ELISA method. The impact of downregulating GAS5 or HIF-1α or both upon hypoxic cells was assessed on the basis of changes in cell viability, apoptosis, and inflammatory response. The activity of JAK1/STAT3 signaling was evaluated through RT-qPCR for mRNA expression. AG490 was introduced to inactivate JAK1/STAT3 pathway and to unveil the impact of JAK1/ STAT3 signaling on GAS5/HIF-1α and cell viability, apoptosis and inflammation in hypoxic cells. Results:The results infer that hypoxia suppressed cell viability, promoted inflammation and apoptosis among H9C2 cells. GAS5 or HIF-1α recorded higher expression in hypoxia-induced cells whereas the cell viability got restored with reduction in inflammation and apoptosis. The downregulation of HIF-1α enhanced the protective effect of knocking down GAS5 in hypoxia H9C2 cells. JAK1/STAT3 signaling pathway got activated in hypoxic cells and was regulated by GAS5 and HIF-1α. The inhibition of signaling pathway increased the cell viability but it decreased both inflammation and apoptosis.Conclusions: GAS5 and HIF-1α could regulate hypoxic injury in H9C2 cells through JAK1/STAT3 signaling pathway. This scenario suggests that the inhibitors of GAS5 and HIF-1α may synergize with AG-490 to protect myocardial cells from hypoxic injury.

show abstract

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice

Yan

et al. 2022

Drug Metabolism Reviews

View full text Add to dashboard Cite

Mechanisms of Cardiotoxicity Associated with Tyrosine Kinase Inhibitors in H9c2 Cells and Mice

Cited by 3 publications

References 0 publications

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

The interplay between HIF-1α and long noncoding GAS5 regulates the JAK1/STAT3 signalling pathway in hypoxia-induced injury in myocardial cells

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice

Contact Info

Product

Resources

About