Mefloquine Inhibited Esophageal Squamous Cells Carcinoma Proliferation by Induction of Mitochondrial Autophagy

Background: Esophageal squamous cell carcinoma (ESCC) still has high rates of incidence and mortality, despite developments in medical technology. Therefore, looking for cancer treatment drugs with high efficiency and low toxicity remains very important. In the previous study, we screened FDA-approved drugs, approved for uses other than tumor treatment, and found that mefloquine (MQ), which is used for prevention and treatment of malaria, inhibited clone formation of ESCC cells. Methods: Proteomics and mass spectrometry (MS) were applied to profile proteome changes in ESCC cells after MQ treatment. KEGG was performed to analyse the significantly down-regulated pathways and proteins. Electron microscopy was used to observe mitochondrial changes in MQ-treated KYSE150 cells. And patient derived xenograft (PDX) mouse model was used to observe the anti-tumor effect of MQ in vivo. Findings: MS analyse showed that various proteins changed in MQ-treated KYSE150 cells. KEGG analyse identified dysregulated pathways and proteins. Among these proteins, SDHC, SDHD, MTCO3 and NDUFV3, all known to be essential enzymes in the mitochondrial respiration chain, were involved in these pathways and were notably down-regulated in MQ-treated cells. Meanwhile, mitochondrial autophagy was verified in MQ-treated cells by electron microscopy. Furthermore, MQ significantly inhibited tumor growth in a patient-derived xenograft mouse model of ESCC. All considered, MQ suppressed ESCC cell proliferation by induction of mitochondrial autophagy. Interpretation: Our data suggested that MQ may be a promising drug for ESCC treatment and chemoprevention. Funding Statement: This work was supported by grants from the National Natural Science Foundations of China (No. 81872335, 81572812, and 81472324) and the Natural Science Foundations of Henan (No. 161100510300). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All procedures involving animals in this study were approved by the Animal Ethics Committee.