title: Curcuminoid EF24 enhances the anti-tumour activity of Akt inhibitor MK-2206 through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in gastric cancer.
abstract: Gastric cancer is one of the leading causes of morbidity and mortality worldwide. Akt is an anti-apoptotic kinase that plays a dynamic role in cell survival and is implicated in the pathogenesis of gastric cancer. MK-2206, the first allosteric inhibitor of Akt, is in clinical trials for a number of cancers. Although preclinical studies showed promise, clinical trials reported it had no effect when given alone at tolerated doses. The aim of our study was to delineate the effects of MK-2206 on gastric cancer cells and explore the ability of combination treatments to enhance the anti-tumour activity of MK-2206.
  
  
  
  SGC-7901, BGC-823 cells and immunodeficient mice were chosen as a model to study the treatment effects. Changes in cell viability, apoptosis and ROS, endoplasmic reticulum stress and mitochondrial dysfunction in the cells were analysed by MTT assays, ROS imaging and FACSCalibur, electron microscopy, JC-1 staining and western blotting.
  
  
  
  MK-2206 induced apoptotic cell death through the generation of ROS. We utilized ROS production to target gastric cancer cells by combining MK-2206 and an ROS inducer EF24. Our in vitro and in vivo xenograft studies showed that combined treatment with MK-2206 and EF24 synergistically induced apoptosis in gastric cancer cells and caused cell cycle arrest. These activities were mediated through ROS generation and the induction of endoplasmic reticulum stress and mitochondrial dysfunction.
  
  
  
  Targeting ROS generation by using a combination of an Akt inhibitor and EF24 could have potential as a therapy for gastric cancer.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Xuanxuan
authors.initials: X
authors.lastname: Dai
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Vinothkumar
authors.initials: V
authors.lastname: Rajamanickam
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Feng
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Zhuge
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D010881:Piperidones; D017382:Reactive Oxygen Species; D051058:Oncogene Protein v-akt