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

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.