Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca2+ overload through the inhibition of phosphoinositide 3-kinase activity

  • Biochem Biophys Res Commun. 2025 Jul 22:771:152027. doi: 10.1016/j.bbrc.2025.152027.
Meiling Gao  1 ,  Zhiling Cheng  1 ,  Wei Yan  2 ,  Zhihan Zhang  3 ,  Ling Zhang  4 ,  Hui Geng  2 ,  Yanfang Xu  5 ,  Congxin Li  6
Affiliations
  • 1. Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China; Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China.
  • 2. Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China.
  • 3. Department of Nutrition, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
  • 4. Department of Pharmacy, Hebei Chest Hospital, Shijiazhuang, Hebei, China.
  • 5. Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China. Electronic address: [email protected].
  • 6. Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China. Electronic address: [email protected].
PMID: 40403685 DOI: 10.1016/j.bbrc.2025.152027
Abstract

Background: Tyrosine kinase inhibitors (TKIs) are commonly used in Cancer treatment, but their off-target effects can lead to serious cardiotoxicity. Our previous studies have revealed that upregulation of phosphoinositide 3-kinase (PI3K) confers considerable protection against calcium (CA2+) disorders and cardiac dysfunction induced by sunitinib. However, the involvement of PI3K inhibition in the prevention of cardiomyocyte contraction induced by Other TKIs remains unclear.

Methods: Herein, we selected three TKIs with different targets and mechanisms, namely, sunitinib, imatinib, and trametinib, and assessed their myocardial toxicity, PI3K activity, and CA2+ regulation in AC16 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Results: All three TKIs induced AC16 cell damage and reduced PI3K expression. These drugs also caused hiPSC-CM injury, increased Reactive Oxygen Species (ROS) release, induced cytoplasmic CA2+ overload, and inhibited cell contraction. Phosphatidylinositol (3,4,5)-trisphosphate pretreatment and adenovirus-mediated p110α overexpression activated PI3K, prevented TKI-induced CA2+ overload and ROS release, and reduced TKI-induced myocardial injury and contraction inhibition.

Conclusions: All three TKIs induced cardiotoxicity by inhibiting PI3K activity.

Keywords
Calcium; Cardiotoxicity; Human induced pluripotent stem cell-derived cardiomyocytes; Phosphoinositide 3-kinase; Tyrosine kinase inhibitor.
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