Cancer Innovation (Feb 2025)

Mitigating Ibrutinib‐Induced Ventricular Arrhythmia and Cardiac Dysfunction With Metformin

  • 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
https://doi.org/10.1002/cai2.151
Journal volume & issue
Vol. 4, no. 1
pp. n/a – n/a

Abstract

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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.

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