10.1021/jm500221p.s001 Yaping Liu Yaping Liu Dongzhu Duan Dongzhu Duan Juan Yao Juan Yao Baoxin Zhang Baoxin Zhang Shoujiao Peng Shoujiao Peng HuiLong Ma HuiLong Ma Yanlin Song Yanlin Song Jianguo Fang Jianguo Fang Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase American Chemical Society 2014 PAO enzyme amine group HL redox homeostasis reactive oxygen species molecule inhibitor cancer chemotherapeutic agent 4 treatment TrxR sensitizes Selectively Targeting Thioredoxin ReductaseThe selenoprotein thioredoxin reductase anticancer drug target 2014-06-26 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Dithiaarsanes_Induce_Oxidative_Stress_Mediated_Apoptosis_in_HL_60_Cells_by_Selectively_Targeting_Thioredoxin_Reductase/2279344 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, <b>4</b>), 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 <b>4</b> 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 <b>4</b> treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by <b>4</b> in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of <b>4</b> as a potential cancer chemotherapeutic agent.