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

Xuanxuan Dai,1,* Junru Zhang,2,* Guilong Guo,1 Yuepiao Cai,3 Ri Cui,3 Changtian Yin,1 Weidong Liu,3 Rajamanickam Vinothkumar,3 Tingting Zhang,3 Guang Liang,3 Xiaohua Zhang1 1Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; 2College of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China; 3Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China *These authors contributed equally to this work 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. Keywords: epidermal growth factor receptor, reactive oxygen species, mono-carbonyl analog of curcumin, ER stress, mitochondrial dysfunction, apoptosis, NSCL