Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer
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Peng Zou1,2, Minxiao Chen1,3, Jiansong Ji4, Weiqian Chen1,4, Xi Chen1, Shilong Ying1, Junru Zhang1, Ziheng Zhang1, Zhiguo Liu1, Shulin Yang2, Guang Liang1
1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
2School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
3Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
4Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
Guang Liang, e-mail: firstname.lastname@example.org
Shulin Yang, e-mail: email@example.com
Keywords: ROS, auranofin, piperlongumine, ER stress, mitochondrial dysfunction
Received: June 12, 2015 Accepted: September 15, 2015 Published: September 28, 2015
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.
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