دورية أكاديمية
Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes
| العنوان: | Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes |
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| المؤلفون: | Huan Wang, Yiming Wang, Jiongyuan Li, Ziyi He, Sarah A. Boswell, Mirra Chung, Fuping You, Sen Han |
| المصدر: | BMC Medicine, Vol 21, Iss 1, Pp 1-21 (2023) |
| بيانات النشر: | BMC |
| سنة النشر: | 2023 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Cardiotoxicity, Tyrosine kinase inhibitor, Transcriptomics, Endoplasmic reticulum stress, Inflammation, Medicine |
| الوصف: | Background Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1741-7015 |
| العلاقة: | https://doi.org/10.1186/s12916-023-02838-2Test; https://doaj.org/toc/1741-7015Test; https://doaj.org/article/96fac43db70b418382c36d847c4bcc4fTest |
| DOI: | 10.1186/s12916-023-02838-2 |
| الإتاحة: | https://doi.org/10.1186/s12916-023-02838-2Test https://doaj.org/article/96fac43db70b418382c36d847c4bcc4fTest |
| رقم الانضمام: | edsbas.2B29784B |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 17417015 |
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| DOI: | 10.1186/s12916-023-02838-2 |