PMID- 27697670 OWN - NLM STAT- MEDLINE DCOM- 20171116 LR - 20211122 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 10 DP - 2016 Dec TI - Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer. PG - 78-89 LID - S2213-2317(16)30133-1 [pii] LID - 10.1016/j.redox.2016.09.006 [doi] AB - Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS) inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER) pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment. CI - Copyright (c) 2016 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Chen, Weiqian AU - Chen W AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. FAU - Zou, Peng AU - Zou P AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China. FAU - Zhao, Zhongwei AU - Zhao Z AD - Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. FAU - Chen, Xi AU - Chen X AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Fan, Xiaoxi AU - Fan X AD - Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. FAU - Vinothkumar, Rajamanickam AU - Vinothkumar R AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Cui, Ri AU - Cui R AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Wu, Fazong AU - Wu F AD - Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. FAU - Zhang, Qianqian AU - Zhang Q AD - Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. FAU - Liang, Guang AU - Liang G AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China. Electronic address: wzmcliangguang@163.com. FAU - Ji, Jiansong AU - Ji J AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China. Electronic address: jjstcty@sina.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160921 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (3,5-bis(2-fluorobenzylidene)piperidin-4-one) RN - 0 (Benzylidene Compounds) RN - 0 (Piperidones) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Redox Biol. 2021 Dec;48:102191. PMID: 34802996 MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/pharmacology MH - Benzylidene Compounds/*administration & dosage/pharmacology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Drug Synergism MH - Endoplasmic Reticulum Stress/drug effects MH - Gene Expression Regulation, Neoplastic MH - Humans MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Mice MH - Piperidones/*administration & dosage/pharmacology MH - Reactive Oxygen Species/*metabolism MH - Sirolimus/*administration & dosage/pharmacology MH - Stomach Neoplasms/*drug therapy/metabolism MH - Xenograft Model Antitumor Assays PMC - PMC5048112 OTO - NOTNLM OT - Antitumor OT - Cytotoxicity OT - EF24 OT - Gastric cancer OT - Oxidative stress OT - Rapamycin EDAT- 2016/10/05 06:00 MHDA- 2017/11/29 06:00 PMCR- 2016/09/21 CRDT- 2016/10/05 06:00 PHST- 2016/08/21 00:00 [received] PHST- 2016/09/10 00:00 [revised] PHST- 2016/09/14 00:00 [accepted] PHST- 2016/10/05 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2016/10/05 06:00 [entrez] PHST- 2016/09/21 00:00 [pmc-release] AID - S2213-2317(16)30133-1 [pii] AID - 10.1016/j.redox.2016.09.006 [doi] PST - ppublish SO - Redox Biol. 2016 Dec;10:78-89. doi: 10.1016/j.redox.2016.09.006. Epub 2016 Sep 21.