Biochemical and biophysical research communications · 2025
Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca2+ overload through the inhibition of phosphoinositide 3-kinase activity.
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Gao Meiling, Cheng Zhiling, Yan Wei, Zhang Zhihan, Zhang Ling, Geng Hui, Xu Yanfang, Li Congxin
Аннотация
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.
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.