title: S-glutathionylated serine proteinase inhibitors as plasma biomarkers in assessing response to redox-modulating drugs.
abstract: Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys(256) of serpin A1 and Cys(263) of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways.
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Grek
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Uys
authors.forename: Yefim
authors.initials: Y
authors.lastname: Manevich
authors.forename: Woodrow J
authors.initials: WJ
authors.lastname: Coker
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pazoles
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood; D019803:Glutathione Disulfide / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*; D010084:Oxidation-Reduction / Q000187:drug effects; D015843:Serpins / Q000097:blood; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D000514:alpha 1-Antichymotrypsin / Q000097:blood*; D000515:alpha 1-Antitrypsin / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; D004338:Drug Combinations; C529375:NOV 002; C516148:SERPINA3 protein, human; D015843:Serpins; D000514:alpha 1-Antichymotrypsin; D000515:alpha 1-Antitrypsin; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide