title: ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer.
abstract: Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.|School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Junru
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Karvannan
authors.initials: K
authors.lastname: Kanchana
authors.affiliation: Department of Oncological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guilong
authors.initials: G
authors.lastname: Guo
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D048670:MAP Kinase Kinase 4; D003474:Curcumin
keywords: ER stress; JNK; ROS; curcumin analog; gastric cancer