title: Dithiaarsanes induce oxidative stress-mediated apoptosis in HL-60 cells by selectively targeting thioredoxin reductase.
abstract: The selenoprotein thioredoxin reductase (TrxR) plays a pivotal role in regulating cellular redox homeostasis and has attracted increasing attention as a promising anticancer drug target. We report here that 2-(4-aminophenyl)-1,3,2-dithiarsinane (PAO-PDT, 4), a potent and highly selective small molecule inhibitor of TrxR, stoichiometrically binds to the C-terminal selenocysteine/cysteine pair in the enzyme in vitro and induces oxidative stress-mediated apoptosis in HL-60 cells. The molecular action of 4 in cells involves inhibition of TrxR, elevation of reactive oxygen species, depletion of cellular thiols, and activation of caspase-3. Knockdown of TrxR sensitizes the cells to 4 treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by 4 in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of 4 as a potential cancer chemotherapeutic agent.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University , Lanzhou, Gansu 730000, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Duan
authors.forename: Juan
authors.initials: J
authors.lastname: Yao
authors.forename: Baoxin
authors.initials: B
authors.lastname: Zhang
authors.forename: Shoujiao
authors.initials: S
authors.lastname: Peng
authors.forename: HuiLong
authors.initials: H
authors.lastname: Ma
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Song
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001152:Arsenicals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C000591344:2-(4-aminophenyl)-1,3,2-dithiarsinane; D000970:Antineoplastic Agents; D001152:Arsenicals; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D013880:Thioredoxin-Disulfide Reductase