Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer

Abstract

// Peng Zou 1, 2 , Minxiao Chen 1, 3 , Jiansong Ji 4 , Weiqian Chen 1, 4 , Xi Chen 1 , Shilong Ying 1 , Junru Zhang 1 , Ziheng Zhang 1 , Zhiguo Liu 1 , Shulin Yang 2 , Guang Liang 1 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China 2 School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China 3 Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China 4 Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China Correspondence to: Guang Liang, e-mail: wzmcliangguang@163.com Shulin Yang, e-mail: bioshuliny@yahoo.com.cn Keywords: ROS, auranofin, piperlongumine, ER stress, mitochondrial dysfunction Received: June 12, 2015      Accepted: September 15, 2015      Published: September 28, 2015 ABSTRACT Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for GC treatment. Auranofin (AF), clinically used to treat rheumatic arthritis, but it exhibited preclinical efficacy in GC cells. By increasing intracellular reactive oxygen species (ROS) levels, AF induces a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in cultured GC cells. Blockage of ROS production reversed AF-induced ER stress and mitochondrial pathways activation as well as apoptosis. In addition, AF displays synergistic lethality with an ROS-generating agent piperlongumine, which is a natural product isolated from the long pepper Piper longum L. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer. More importantly, it reveals that increased ROS generation might be an effective strategy in treating human gastric cancer.