Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo.
Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo.
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磷酸肌醇 3-激酶的上调可预防舒尼替尼诱导的体外和体内心脏毒性
DOI：
10.1007/s00204-019-02448-z
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Yanfang Xu
中科院分区：
文献类型：
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作者：
Congxin Li;Ruya Zou;Hua Zhang;Yuhong Wang;Bo Qiu5;Suhua Qiu1;Wei Wang;Yanfang Xu
舒尼替尼（SNT）是一种多靶点受体酪氨酸激酶抑制剂，已被FDA批准用于癌症治疗。然而，其心脏毒性限制了其临床应用，并且没有有效的治疗方法。作为一种宽带激酶抑制剂，SNT也可能影响心脏功能所必需的几种激酶的功能，如钙调蛋白依赖性蛋白激酶（CaMKII）、环AMP依赖性蛋白激酶（PKA）、AMP活化蛋白激酶（AMPK）和磷酸肌醇3激酶（PI 3 K）。在这项研究中，我们研究了是否可以通过阻断SNT诱导的相应信号通路的改变来预防SNT诱导的心脏毒性。在人诱导多能干细胞衍生的心肌细胞中，SNT（0.5-20 µmol/L）以浓度依赖性方式抑制心肌细胞的收缩性，并且PIP 3（1 µmol/L）应用或PI 3 K过表达可阻止抑制作用。相反，CaMKII抑制剂KN-93（50 nmol/L）、PKA抑制剂H89（1 µmol/L）、AMPK激活剂二甲双胍（2 mmol/L）和5-氨基咪唑-4-甲酰胺1-b-d-呋喃核糖苷（2 mmol/L）的影响可忽略不计。小鼠口服SNT（40 mg/kg/d）2周后，PI 3 K活性和心功能逐渐降低，Cav1.2和SERCA的表达和活性显著降低。在小鼠中通过腺相关病毒9介导的基因递送的心脏特异性PI 3 K过表达防止了SNT诱导的心脏功能、钙瞬变、钙电流和Cav1.2表达的降低。总之，我们的数据表明，增加PI 3 K活性对SNT诱导的钙处理不当和收缩功能障碍具有保护作用。心脏特异性PI 3 K激活可能是治疗癌症患者SNT心脏毒性的有效治疗方法。
Sunitinib (SNT) is a multi-targeted receptor tyrosine kinase inhibitor that has been approved by the FDA for cancer therapy. However, its cardiotoxicity has limited the clinical applicability with no effective therapeutic approach available. As a broadband kinase inhibitor, the function of several kinases that are essential to cardiac function might also be affected by SNT, such as calmodulin-dependent protein kinase (CaMKII), cyclic-AMP-dependent protein kinases (PKA), AMP-activated protein kinase (AMPK), and phosphoinositide 3 kinase (PI3K). In this study, we investigated whether SNT-induced cardiotoxicity could be prevented by blocking SNT-induced alteration in the corresponding signaling pathways. In human induced pluripotent stem cell-derived cardiomyocytes, SNT (0.5–20 µmol/L) inhibited contractility of cardiomyocytes in a concentration-dependent manner, and the inhibitory effect was prevented either by PIP3 (1 µmol/L) application or PI3K overexpression. On the contrary, the CaMKII inhibitor KN-93 (50 nmol/L), PKA inhibitor H89 (1 µmol/L), and AMPK activators metformin (2 mmol/L) and 5-aminoimidazole-4-carboxamide 1-b-d-ribofuranoside (2 mmol/L) presented negligible effects. Oral SNT administration (40 mg/kg/day) in mice progressively decreased the PI3K activity and cardiac function in 2 weeks with a significant decrease in the expression and activity of Cav1.2 and SERCA. Cardiac-specific PI3K overexpression through adeno-associated virus 9-mediated gene delivery in mice prevented SNT-induced reduction in cardiac function, calcium transient, calcium current, and Cav1.2 expression. In summary, our data indicate that increased PI3K activity is protective against SNT-induced calcium mishandling and contractile dysfunction. Cardiac-specific PI3K activation could be an effective therapeutic approach to treat SNT cardiotoxicity in patients with cancer.