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Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin.

Li, Pengsha, Liu, Daiqi, Gao, Pan, Yuan, Ming, Zhao, Zhiqiang, Zhang, Yue, Zhou, Zandong, Zhang, Qingling, Yuan, Meng, Liu, Xing, and others. (2024) Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin. Cancer Innovation, 4 (1). Article Number e151. E-ISSN 2770-9183. (doi:10.1002/cai2.151) (KAR id:107910)

Abstract

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.

Item Type: Article
DOI/Identification number: 10.1002/cai2.151
Uncontrolled keywords: Metformin, ventricular arrhythmia, Ibrutinib, Pi3k‐Akt Pathway
Subjects: R Medicine
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Funders: National Natural Science Foundation of China (https://ror.org/01h0zpd94)
SWORD Depositor: JISC Publications Router
Depositing User: JISC Publications Router
Date Deposited: 27 Nov 2024 16:06 UTC
Last Modified: 29 Nov 2024 09:37 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/107910 (The current URI for this page, for reference purposes)

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