ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer
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Peng Zou1,2, Junru Zhang1, Yiqun Xia3, Karvannan Kanchana1, Guilong Guo4, Wenbo Chen1, Yi Huang1, Zhe Wang1, Shulin Yang2 and Guang Liang1
1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
2 School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China
3 Department of Digestive Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
4 Department of Oncological Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Guang Liang, email:
Shulin Yang, email:
Keywords: Gastric cancer, ROS, Curcumin analog, ER stress, JNK
Received: September 15, 2014 Accepted: January 03, 2015 Published: January 21, 2015
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.
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