Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China.
Hum Exp Toxicol. 2021 Dec;40(12_suppl):S49-S62. doi: 10.1177/09603271211030554. Epub 2021 Jul 5.
Almonertinib, a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective to EGFR T790M-mutant non-small cell lung cancer (NSCLC). However, there is no available information on the form and molecular mechanism of Almonertinib-induced death in NSCLC cells. Herein, CCK-8 and colony formation assays, flow cytometry, electron microscopy, and western blots assay showed that Almonertinib inhibited NSCLC cells growth and proliferation by inducing apoptosis and autophagy which can be inhibited by a broad spectrum of caspase inhibitor Z-VAD-fmk or autophagy inhibitor chloroquine. Importantly, Almonertinib-induced autophagy was cytoprotective in NSCLC cells, and the blockade of autophagy improved cell apoptosis. In addition, Almonertinib increased reactive oxygen species (ROS) generation and clearance of ROS through pretreatment with N-acetyl-L-cysteine (NAC) inhibited the decrease of cell viability, apoptosis and increase of LC3-II induced by Almonertinib. The results of Western blot showed that both EGFR activity and downstream signaling pathways were inhibited by Almonertinib. Taken together, these findings indicated that Almonertinib induced apoptosis and autophagy by promoting ROS production in NSCLC cells.
阿美替尼，一种新型第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，对 EGFR T790M 突变型非小细胞肺癌（NSCLC）具有高度选择性。然而，目前尚无关于阿美替尼诱导 NSCLC 细胞死亡的形式和分子机制的信息。在此，CCK-8 和集落形成实验、流式细胞术、电子显微镜和 Western blot 实验表明，阿美替尼通过诱导细胞凋亡和自噬来抑制 NSCLC 细胞的生长和增殖，这种诱导作用可以被广谱半胱天冬酶抑制剂 Z-VAD-fmk 或自噬抑制剂氯喹所抑制。重要的是，阿美替尼诱导的自噬对 NSCLC 细胞具有细胞保护作用，而自噬的阻断则可增强细胞凋亡。此外，阿美替尼通过预处理 N-乙酰-L-半胱氨酸（NAC）增加活性氧（ROS）的产生并清除 ROS，从而抑制了阿美替尼引起的细胞活力下降、细胞凋亡增加和 LC3-II 的增加。Western blot 的结果表明，阿美替尼抑制了 EGFR 的活性及其下游信号通路。综上所述，这些发现表明阿美替尼通过促进 NSCLC 细胞中 ROS 的产生来诱导细胞凋亡和自噬。
