Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China.
Thorac Cancer. 2022 May;13(10):1513-1524. doi: 10.1111/1759-7714.14425. Epub 2022 Apr 16.
Lung cancer is one of the most lethal cancers worldwide. Cisplatin, a widely used anti-lung cancer drug, has been limited in clinical application due to its drug resistance. Medicines targeting mitochondrial electron transport chain (ETC) complexes may be effective candidates for cisplatin-based chemotherapy.
In this study, the small molecule drug library from Food and Drug Administration FDA was used to screen for medicines targeting ETC. MTT and colony formation assays were used to investigate cell proliferation. Flow cytometry was employed to analyze cell cycle, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential. Wound scratch and transwell assays were used to detect migration and invasion abilities. The activities of the ETC complex were tested using kits. Western blot analysis was used to investigate the expressions of related proteins. A mouse xenograft model was constructed to verify the antitumor effect in vivo.
The results showed that mubritinib can reduce the activation of the PI3K/mTOR signal pathway, disrupt mitochondrial function, significantly increase ROS levels and induce oxidative stress, and ultimately exert its antitumor effect against non-small cell lung cancer (NSCLC) both in vivo and in vitro. In addition, the combination of cisplatin and mubritinib can improve the tumor-suppressive effect of cisplatin.
Mubritinib can upregulate intracellular ROS concentration and cell apoptosis, inhibit the PI3K signaling pathway and interfere with the function of mitochondria, thus reducing cell proliferation and increasing ROS induced apoptosis by reducing the activation of Nrf2 by PI3K.
肺癌是全球最致命的癌症之一。顺铂是一种广泛应用于治疗肺癌的药物，但由于其耐药性，在临床应用中受到限制。靶向线粒体电子传递链（ETC）复合物的药物可能是顺铂为基础的化疗的有效候选药物。
本研究利用美国食品和药物管理局（FDA）的小分子药物库筛选靶向 ETC 的药物。MTT 和集落形成实验用于研究细胞增殖。流式细胞术用于分析细胞周期、凋亡、活性氧（ROS）和线粒体膜电位。划痕和 Transwell 实验用于检测迁移和侵袭能力。使用试剂盒测试 ETC 复合物的活性。Western blot 分析用于研究相关蛋白的表达。构建小鼠异种移植模型以验证体内的抗肿瘤作用。
结果表明，mubritinib 可以降低 PI3K/mTOR 信号通路的激活，破坏线粒体功能，显著增加 ROS 水平并诱导氧化应激，从而在体内和体外发挥其对非小细胞肺癌（NSCLC）的抗肿瘤作用。此外，顺铂和 mubritinib 的联合应用可以提高顺铂的肿瘤抑制作用。
Mubritinib 可以上调细胞内 ROS 浓度和细胞凋亡，抑制 PI3K 信号通路并干扰线粒体功能，从而减少细胞增殖，并通过降低 PI3K 对 Nrf2 的激活来增加 ROS 诱导的凋亡。
