The Novel Autophagy Inhibitor Alpha-Hederin Promoted Paclitaxel Cytotoxicity by Increasing Reactive Oxygen Species Accumulation in Non-Small Cell Lung Cancer Cells

• Main Authors: Yujuan Zhan, Kun Wang, Qiao Li, Yidan Zou, Bonan Chen, Qing Gong, Hiuting Idy HO, Ting Yin, Fangyuan Zhang, Yuhua Lu, Weijie Wu, Yilin Zhang, Yuhui Tan, Biaoyan Du, Xiaodong Liu, Jianyong Xiao
• Format: Article
• Language: English
• Published: MDPI AG 2018-10-01
• Series: International Journal of Molecular Sciences
• Subjects: alpha-hederin; autophagy inhibition; non-small cell lung cancer; chemotherapy; paclitaxel; synergistic effect
• Online Access: http://www.mdpi.com/1422-0067/19/10/3221

Chemoresistance is a major limiting factor that impairs the outcome of non-small cell lung cancer (NSCLC) chemotherapy. Paclitaxel (Tax) induces protective autophagy in NSCLC cells, leading to the development of drug resistance. We recently identified a new autophagy inhibitor (alpha-hederin) and hypothesized that it may promote the killing effect of Tax on NSCLC cells. We found that alpha-hederin (α-Hed) could block late autophagic flux in NSCLC cells by altering lysosomal pH and inhibiting lysosomal cathepsin D maturation. Combination treatment of α-Hed and Tax synergistically reduced NSCLC cell proliferation and increased NSCLC cell apoptosis compared with treatment with α-Hed or Tax alone. Furthermore, α-Hed plus Tax enhanced the accumulation of intracellular reactive oxygen species (ROS) in NSCLC cells, while the ROS inhibitor N-acetylcysteine reversed the inhibitory effect of the combination treatment. Our findings suggest that α-Hed can increase the killing effect of Tax on NSCLC cells by promoting ROS accumulation, and that combining α-Hed with classical Tax represents a novel strategy for treating NSCLC.