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

Abstract

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.

Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity

“…This is not surprising, since cisplatin has not previously been shown to cause inhibition of any respiratory chain complexes. In addition, some inhibitors of the respiratory chain are used in co-chemotherapy with cisplatin to increase the level of oxidative stress to damage tumor cells [ 29 ]. However, our data do not contradict the claim that cisplatin causes oxidative stress in the kidneys.…”

Stellera chamaejasme L. extracts in the treatment of glioblastoma cell lines: Biological verification based on a network pharmacology approach

“…MAPK9 plays an important role in the regulatory biological clock by phosphorylating the ARNTL/BMAL1 heterodimers ( 39 ). Transcription factor Nrf2 plays an important role in cellular oxidative stress ( 40 ), and its transcriptional activation has been related to anti-ferroptosis ( 41 ). Nrf2 overexpression can cause chemical-sensitive tumor cells to resist ferroptosis inducers by inhibiting KEAP1 overexpression ( 42 ).…”

Molecular Recognition Study toward the Mitochondrial Electron Transport Chain Inhibitor Mubritinib and Human Serum Albumin

“…7 Therefore, it is of great interest to the biomedical sciences to understand the pharmacological effects of mitochondrial respiratory chain complexes inhibitors such as MUB, taking into account the limited knowledge about the mechanisms of action of this class of drugs currently. 6 MUB is known to be efficient in the treatment of acute myeloid leukemia, 2 breast cancer, 8 spinal cord injury, 9 gastric cancer, 10 chronic allergies, 11 and lung cancer, 12 among other diseases. Considering the HER2 molecular target, MUB has reached phase I clinical trials for solid tumor treatment.…”

“…MUB is known to be efficient in the treatment of acute myeloid leukemia, breast cancer, spinal cord injury, gastric cancer, chronic allergies, and lung cancer, among other diseases. Considering the HER2 molecular target, MUB has reached phase I clinical trials for solid tumor treatment .…”