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

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收录情况： ◇ SCIE

作者：
Gao Meiling[1,2] * ; Cheng Zhiling[1,2] ; Yan Wei[1] ; Zhang Zhihan[3] ; Zhang Ling[4] ; Geng Hui[1] ; Xu Yanfang[2] ; Li Congxin[1] ;
机构： [1]Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China [2]Hebei Medical University, No. 361 Zhongshan East Road, Chang'an 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.
出处：
DOI： 10.1016/j.bbrc.2025.152027
ISSN：

关键词： Phosphoinositide 3-kinase Tyrosine kinase inhibitor Calcium Human induced pluripotent stem cell-derived cardiomyocytes Cardiotoxicity

摘要：
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.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).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.All three TKIs induced cardiotoxicity by inhibiting PI3K activity.Copyright © 2025 Elsevier Inc. All rights reserved.

基金：
This study was supported by the National Natural Science Foundation of China (No. 82003878), the Natural Science Foundation of Hebei Province (No. H2024206062), the Medical Science Research Project of Hebei (No. 20250074), and the Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine (No. 2024285).
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外文
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出版当年[2025]版：
大类 | 4 区 生物学
小类 | 4 区 生化与分子生物学 4 区 生物物理
最新[2025]版：
大类 | 4 区 生物学
小类 | 4 区 生化与分子生物学 4 区 生物物理
JCR分区：
出版当年[2024]版：
Q3 BIOPHYSICS Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
最新[2024]版：
Q3 BIOPHYSICS Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

影响因子： 最新[2024版] 最新五年平均 出版当年[2025版] 出版当年五年平均 出版前一年[2024版]

第一作者：
第一作者机构： [1]Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China [2]Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China.
通讯作者：
推荐引用方式(GB/T 7714)：
Gao Meiling,Cheng Zhiling,Yan Wei,et al.Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca2+ overload through the inhibition of phosphoinositide 3-kinase activity[J].Biochemical And Biophysical Research Communications.2025,771:152027.doi:10.1016/j.bbrc.2025.152027.
APA：
Gao Meiling,Cheng Zhiling,Yan Wei,Zhang Zhihan,Zhang Ling...&Li Congxin.(2025).Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca2+ overload through the inhibition of phosphoinositide 3-kinase activity.Biochemical And Biophysical Research Communications,771,
MLA：
Gao Meiling,et al."Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca2+ overload through the inhibition of phosphoinositide 3-kinase activity".Biochemical And Biophysical Research Communications 771.(2025):152027

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