title: Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin I.
abstract: OBJECTIVE
  The intrinsic increase of reactive oxygen species (ROS) production in cancer cells after malignant transformation frequently induces redox adaptation, leading to enhanced antioxidant capacity. Peroxiredoxin I (PrxI), an enzyme responsible for eliminating hydrogen peroxide, has been found to be elevated in many types of cancer cells. Since overexpression of PrxI promoted cancer cells' survival and resistance to chemotherapy and radiotherapy, PrxI has been proposed as a therapeutic target for anticancer drugs. In this study, we aimed to investigate the anticancer efficacy of a small molecule inhibitor of PrxI.
  
  
  RESULTS
  By a high-throughput screening approach, we identified AMRI-59 as a potent inhibitor of PrxI. AMRI-59 increased cellular ROS, leading to the activation of both mitochondria- and apoptosis signal-regulated kinase-1-mediated signaling pathways, resulting in apoptosis of A549 human lung adenocarcinoma. AMRI-59 caused no significant changes in ROS level, proliferation, and apoptosis of PrxI-knockdown A549 cells by RNA interference. PrxI overexpression or N-acetylcysteine pretreatment abrogated AMRI-59-induced cytotoxicity in A549 cells. AMRI-59 rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells. Moreover, significant antitumor activity of AMRI-59 was observed in mouse tumor xenograft model implanted with A549 cells with no apparent acute toxicity.
  
  
  METHODS
  This study offers preclinical proof-of-concept for AMRI-59, a lead small molecule inhibitor of PrxI, as an anticancer agent.
  
  
  CONCLUSIONS
  Our results highlight a promising strategy for cancer therapy that preferentially eradicates cancer cells by targeting the PrxI-mediated redox-dependent survival pathways.
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.|2 Brain Korea 21 PLUS Project for Medical Science, Yonsei University , Seoul, Republic of Korea.
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Baek
authors.affiliation: 3 College of Life Sciences and Biotechnology, Korea University , Seoul, Republic of Korea.
authors.forename: Jail
authors.initials: J
authors.lastname: Goo
authors.affiliation: 4 College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Yoonho
authors.initials: Y
authors.lastname: Shin
authors.affiliation: 5 Laboratory of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences , Seoul, Republic of Korea.
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Jang
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Su Bin
authors.initials: SB
authors.lastname: Wang
authors.affiliation: 6 Division of Life Sciences, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.|7 College of Pharmacy, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: 5 Laboratory of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences , Seoul, Republic of Korea.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.affiliation: 4 College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: 3 College of Life Sciences and Biotechnology, Korea University , Seoul, Republic of Korea.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: 8 Yonsei Biomedical Research Institute, Yonsei University College of Medicine , Seoul, Republic of Korea.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: 1 Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul, Republic of Korea.|7 College of Pharmacy, Ewha Womans University , Seoul, Republic of Korea.
authors.forename: Tong-Shin
authors.initials: TS
authors.lastname: Chang
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000612429:AMRI-59; D000098:Acetophenones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D054464:Peroxiredoxins