EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: In Vivo and in Vitro Rat Studies
EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: In Vivo and in Vitro Rat Studies
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DOI：
10.1021/acs.chemrestox.0c00005
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发表时间：
2020-07-20
影响因子：
4.1
通讯作者：
Korashy, Hesham M.
中科院分区：
文献类型：
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作者：
Alhoshani, Ali;Alanazi, Fawaz E.;Korashy, Hesham M.
吉非替尼 (GEF) 是一种选择性表皮生长因子受体 (EGFR) 抑制剂，用于治疗非小细胞肺癌。然而，心脏毒性病例的报道很少。然而，介导 GEF 抗癌活性的 PTEN/Akt/FoxO3a 通路在 GEF 心脏毒性中的作用仍不清楚。为此，利用体外 H9c2 细胞和体内大鼠心肌细胞作为研究模型。用 GEF 处理 H9c2 细胞和 Sprague-Dawley 大鼠，显着诱导 mRNA 和蛋白质水平的肥大和细胞凋亡标志物的表达，同时血浆肌钙蛋白水平增加。这伴随着 H9c2 细胞自噬和线粒体功能障碍的诱导。 GEF 抑制体外和体内大鼠心肌细胞的心脏 EGFR 活性和 Akt 细胞含量，增加 PTEN 和 FoxO3a 基因表达和细胞含量。重要的是，用 PI3K/Akt 抑制剂处理 H9c2 细胞会增加与 GEF 心脏毒性增强相关的 PTEN 和 FoxO3a mRNA 表达。此外，通过使用 LC-MS/MS，我们发现 GEF 在大鼠心脏微粒体中代谢为一种氰化物和两种甲氧基胺加合物反应性代谢物，其中它们的形成被 CYP1A1 抑制剂 α-萘黄酮完全阻断。目前的研究结论是，GEF 通过调节心脏 PTEN/AKT/FoxO3a 通路的表达和功能以及 CYP1A1 介导的反应性代谢物的形成来诱导心脏毒性。
Gefitinib (GEF) is a selective inhibitor of the epidermal growth factor receptor (EGFR) used to treat non-small cell lung cancer. Yet, few cases of cardiotoxicity have been reported. However, the role of the PTEN/Akt/FoxO3a pathway, which mediates GEF anticancer activity, in GEF cardiotoxicity remains unclear. For this purpose, in vitro H9c2 cells and in vivo rat cardiomyocytes were utilized as study models. Treatment of H9c2 cells and Sprague-Dawley rats with GEF significantly induced the expression of hypertrophic and apoptotic markers at mRNA and protein levels with an increased plasma level of troponin. This was accompanied by induction of autophagy and mitochondrial dysfunction in H9c2 cells. Inhibition of cardiac EGFR activity and Akt cellular content of in vitro and in vivo rat cardiomyocytes by GEF increased PTEN and FoxO3a gene expression and cellular content. Importantly, treatment of H9c2 cells with PI3K/Akt inhibitor increased PTEN and FoxO3a mRNA expression associated with potentiation of GEF cardiotoxicity. In addition, by using LC-MS/MS, we showed that GEF is metabolized in the rat heart microsomes into one cyanide- and two methoxylamine-adduct reactive metabolites, where their formation was entirely blocked by CYP1A1 inhibitor, alpha-naphthoflavone. The current study concludes that GEF induces cardiotoxicity through modulating the expression and function of the cardiac PTEN/AKT/FoxO3a pathway and the formation of CYP1A1-mediated reactive metabolites.