A mono-carbonyl analog of curcumin induces apoptosis in drug-resistant EGFR-mutant lung cancer through the generation of oxidative stress and mitochondrial dysfunction

摘要

Introduction: Targeted therapies using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations, leading to the approval of gefitinib and erlotinib as standard first-line clinical treatment. Inevitably, a considerable proportion of patients develop resistance to EGFR-TKIs due to the acquisition of secondary mutations within EGFR. Therefore, alternative strategies to target NSCLC are desperately needed. Materials and methods: In this study, we have evaluated the effect of a reactive oxygen species (ROS)-inducing agent WZ35, a mono-carbonyl analog of curcumin, to target an inherent biological property of cancer cells, increased oxidative stress. To study whether WZ35 can inhibit NSCLC tumorigenesis, we used gefitinib- and erlotinib-resistant cell line H1975. Results: In this study, we show that WZ35 treatment dramatically decreases cell viability and induces apoptosis in H1975 cells through the generation of ROS. We also found that the -antitumor activity of WZ35 involved ROS-mediated activation of the endoplasmic reticulum stress pathway and mitochondrial dysfunction. Furthermore, WZ35 significantly inhibited H1975 xenograft tumor growth through the inhibition of cell proliferation and induction of apoptosis. Discussion: These findings show that WZ35 may be a promising candidate for the treatment of EGFR-TKI-resistant NSCLC.