Dithiaarsanes induce oxidative stress-mediated apoptosis in HL-60 cells by selectively targeting thioredoxin reductase

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.