Mitigating ibrutinib‐induced ventricular arrhythmia and cardiac dysfunction with metformin
Journal article
Li, Pengsha, Liu, Daiqi, Gao, P., Yuan, Ming, Zhao, Zhiqiang, Zhang, Yue, Zhou, Zandong, Zhang, Qingling, Yuan, Meng, Liu, Xing, Tse, Gary, Li, Guangping, Bao, Qiankun and Liu, Tong 2024. Mitigating ibrutinib‐induced ventricular arrhythmia and cardiac dysfunction with metformin. Cancer Innovation. 4 (1). https://doi.org/10.1002/cai2.151
| Authors | Li, Pengsha, Liu, Daiqi, Gao, P., Yuan, Ming, Zhao, Zhiqiang, Zhang, Yue, Zhou, Zandong, Zhang, Qingling, Yuan, Meng, Liu, Xing, Tse, Gary, Li, Guangping, Bao, Qiankun and Liu, Tong |
|---|---|
| Abstract | AbstractBackgroundIbrutinib 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.MethodsThe 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.ResultsC57BL/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.ConclusionThe 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. |
| Keywords | Metformin; Ventricular arrhythmia; Ibrutinib; Pi3k‐Akt Pathway |
| Year | 2024 |
| Journal | Cancer Innovation |
| Journal citation | 4 (1) |
| Publisher | Wiley |
| ISSN | 2770-9191 |
| 2770-9183 | |
| Digital Object Identifier (DOI) | https://doi.org/10.1002/cai2.151 |
| Official URL | https://onlinelibrary.wiley.com/doi/full/10.1002/cai2.151 |
| Funder | National Natural Science Foundation of China |
| Publication dates | |
| 01 Feb 2025 | |
| Online | 13 Nov 2024 |
| Publication process dates | |
| Deposited | 27 Nov 2024 |
| Accepted | 06 Jun 2024 |
| Publisher's version | License File Access Level Open |
| Output status | Published |
| Additional information | Publications router. |
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https://repository.canterbury.ac.uk/item/99v62/mitigating-ibrutinib-induced-ventricular-arrhythmia-and-cardiac-dysfunction-with-metformin
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