Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function

• Published in: Thoracic cancer 2022-05, Vol.13 (10), p.1513-1524
• Main Authors: Dong, Jingyao, Zhu, Dongshan, Chen, Mengmeng, Wang, Taiwei, Gao, Yan, Liu, Wei
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Cisplatin - pharmacology; Cisplatin - therapeutic use; FDA approval; Humans; Laboratory animals; Lung cancer; Lung Neoplasms - pathology; Mice; Mitochondria; Mitochondria - metabolism; mitochondrial electron transport chain; mubritinib; Original; Oxazoles; Phosphatidylinositol 3-Kinases - metabolism; PI3K/mTOR pathway; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiration; ROS; Triazoles; Tumors
• ISSN: 1759-7706; 1759-7714
• DOI: 10.1111/1759-7714.14425

Background 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. Methods 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. Results 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. Conclusion 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. In addition to directly causing DNA damage, cisplatin can also lead to DNA damage by inducing ROS production, thus leading to apoptosis. However, ROS can activate Nrf2, which in turn leads to the increase of HO‐1, GPX4 and other antioxidants, which feedback the inhibitory effect of ROS. In addition, the highly expressed PI3K/Akt/mTOR signaling pathway in tumor cells promotes energy generation and cell proliferation by promoting mitochondrial function. PI3K also inhibited Nrf2 activation. This might be one of the important mechanisms of endogenous drug resistance of cisplatin. Mubritinib can upregulate intracellular ROS concentration and cell apoptosis on the one hand, while on the other hand, it can inhibit the PI3K signaling pathway and interfere with the function of mitochondria, thus reducing the