Pengsha Li, Daiqi Liu, Pan Gao, Ming Yuan, Zhiqiang Zhao, Yue Zhang, Zandong Zhou, Qingling Zhang, Meng Yuan, Xing Liu, Gary Tse, Guangping Li, Qiankun Bao, Tong Liu
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Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail-cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways, along with apoptosis markers.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib-induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K-AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K-AKT activity, which contributed to the improvement of cardiac function.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K-AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.</p>\n </section>\n </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"4 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560382/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin\",\"authors\":\"Pengsha Li, Daiqi Liu, Pan Gao, Ming Yuan, Zhiqiang Zhao, Yue Zhang, Zandong Zhou, Qingling Zhang, Meng Yuan, Xing Liu, Gary Tse, Guangping Li, Qiankun Bao, Tong Liu\",\"doi\":\"10.1002/cai2.151\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. 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引用次数: 0
摘要
背景介绍伊布替尼是一种靶向布鲁顿酪氨酸激酶的一线药物,用于治疗B细胞癌。然而,伊布替尼诱导的心脏毒性是限制其临床应用的主要副作用。本研究旨在探讨伊布替尼诱发心脏毒性的机制,并评估二甲双胍的保护作用:研究利用雄性C57BL/6 J小鼠,以30毫克/千克/天的剂量通过口服灌胃给药伊布替尼,连续4周诱导心脏毒性。二甲双胍的剂量为200毫克/千克/天,口服5周,在伊布替尼治疗前1周开始。使用超声心动图和电生理研究(包括表面心电图和心外膜电图)评估心脏功能。使用尾袖带系统测量血压。进行了 Western 印迹分析,以评估 PI3K-AKT 和 AMPK 通路以及细胞凋亡标记物的活性:C57BL/6 J小鼠接受伊布替尼治疗4周,以评估其对心脏功能的影响。我们观察到,伊布替尼会诱发室性心律失常和传导异常,同时降低左室射血分数。此外,二甲双胍可逆转伊布替尼诱导的心脏毒性。从机理上讲,伊布替尼降低了PI3K-AKT活性,导致心肌细胞凋亡。服用二甲双胍可上调AMPK和PI3K-AKT的活性,从而改善心脏功能:研究得出结论:二甲双胍通过增强AMPK和PI3K-AKT通路的活性,有效缓解了伊布替尼诱导的心脏毒性,包括室性心律失常和心功能不全。这些研究结果表明,二甲双胍有可能作为一种治疗策略,防止与伊布替尼治疗相关的心脏不良反应,为改善接受B细胞癌症治疗的患者的心血管安全性提供了一种前景广阔的方法。
Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin
Background
Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. However, cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use. This study aimed to investigate the mechanism of ibrutinib-induced cardiotoxicity and evaluate the protective role of metformin.
Methods
The study utilized male C57BL/6 J mice, which were administered ibrutinib at a dosage of 30 mg/kg/day via oral gavage for 4 weeks to induce cardiotoxicity. Metformin was administered orally at 200 mg/kg/day for 5 weeks, starting 1 week before ibrutinib treatment. Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail-cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways, along with apoptosis markers.
Results
C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib-induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K-AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K-AKT activity, which contributed to the improvement of cardiac function.
Conclusion
The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K-AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.