title: Oxidation of structural cysteine residues in thioredoxin 1 by aromatic arsenicals enhances cancer cell cytotoxicity caused by the inhibition of thioredoxin reductase 1.
abstract: Thioredoxin systems, composed of thioredoxin reductase (TrxR), thioredoxin (Trx) and NADPH, play important roles in maintaining cellular redox homeostasis and redox signaling. Recently the cytosolic Trx1 system has been shown to be a cellular target of arsenic containing compounds. To elucidate the relationship of the structure of arsenic compounds with their ability of inhibiting TrxR1 and Trx1, and cytotoxicity, we have investigated the reaction of Trx1 system with seven arsenic trithiolates: As(Cys)3, As(GS)3, As(Penicillamine)3, As(Mercaptoethanesulfonate)3, As(Mercaptopurine)3, As(2-mercaptopyridine)3 and As(2-mercaptopyridine N-oxide)3. The cytotoxicity of these arsenicals was consistent with their ability to inhibit TrxR1 in vitro and in cells. Unlike other arsenicals, As(Mercaptopurine)3 which did not show inhibitory effects on TrxR1 had very weak cytotoxicity, indicating that TrxR1 is a reliable drug target for arsenicals. Moreover, the two aromatic compounds As(2-mercaptopyridine)3 and As(2-mercaptopyridine N-oxide)3 showed stronger cytotoxicity than the others. As(2-mercaptopyridine)3 which selectively oxidized two structural cysteines (Cys62 and Cys69) in Trx1 showed mild improvement in cytotoxicity. As(2-mercaptopyridine N-oxide)3 oxidized all the Cys residues in Trx1, exhibiting the strongest cytotoxicity. Oxidation of Trx1 by As(2-mercaptopyridine)3 and As(2-mercaptopyridine N-oxide)3 affected electron transfer from NADPH and TrxR1 to peroxiredoxin 1 (Prx1), which could result in the reactive oxygen species elevation and trigger cell death process. These results suggest that oxidation of structural cysteine residues in Trx1 by aromatic group in TrxR1-targeting drugs may sensitize tumor cells to cell death, providing a novel approach to regulate cellular redox signaling and also a basis for rational design of new anticancer agents.
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: grace.zhangxu@gmail.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: Jun.lu@ki.se.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: xiaoyuan.ren@ki.se.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Ren
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: yataodu@gmail.com.
authors.forename: Yatao
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE 171 76 Stockholm, Sweden. Electronic address: yujuan.zheng@ki.se.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, University of Patras, Rio 26500, Greece. Electronic address: ioannou@chemistry.upatras.gr.
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Ioannou
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Electronic address: arne.holmgren@ki.se.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
mesh_terms: D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects*; D003545:Cysteine / Q000737:chemistry*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D009249:NADP / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D009249:NADP; D054464:Peroxiredoxins; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D003545:Cysteine
keywords: Arsenical; Cytotoxicity; Oxidative stress; Thioredoxin; Thioredoxin reductase