title: Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage.
abstract: Recent studies have shown that many types of cancer cells have increased levels of reactive oxygen species (ROS) and enhance antioxidant capacity as an adaptation to intrinsic oxidative stress, suggesting that cancer cells are more vulnerable to oxidative insults and are more dependent on antioxidant systems compared with normal cells. Thus, disruption of redox homeostasis caused by a decline in antioxidant capacity may provide a method for the selective death of cancer cells. Here we show that ROS-mediated selective death of tumor cells can be caused by inhibiting sulfiredoxin (Srx), which reduces hyperoxidized peroxiredoxins, leading to their reactivation. Srx inhibitor increased the accumulation of sulfinic peroxiredoxins and ROS, which led to oxidative mitochondrial damage and caspase activation, resulting in the death of A549 human lung adenocarcinoma cells. Srx depletion also inhibited the growth of A549 cells like Srx inhibition, and the cytotoxic effects of Srx inhibitor were considerably reversed by Srx overexpression or antioxidants such as N-acetyl cysteine and butylated hydroxyanisol. Moreover, Srx inhibitor rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells and significantly suppressed the growth of A549 xenografts without acute toxicity. Our results suggest that Srx might serve as a novel therapeutic target for cancer treatment based on ROS-mediated cell death.
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Hojin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Gong-Rak
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Baek
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Jo
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Seong-Eun
authors.initials: SE
authors.lastname: Hong
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Jiae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Hye In
authors.initials: HI
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Korea University, Sejong 339-700, South Korea.
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.affiliation: College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, South Korea.
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Tong-Shin
authors.initials: TS
authors.lastname: Chang
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea. Electronic address: jeongw@ewha.ac.kr.
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000612188:(4-(((4-(4-(2-chlorophenyl)-1-piperazinyl)-6-phenyl-2-pyrimidinyl)thio)methyl)-benzoic acid); D000970:Antineoplastic Agents; D001565:Benzoates; D017382:Reactive Oxygen Species; D050862:Oxidoreductases Acting on Sulfur Group Donors; C504024:SRXN1 protein, human
keywords: Apoptosis; Cancer; Mitochondrial damage; Reactive oxygen species; Sulfiredoxin