Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase
journal contributionposted on 26.06.2014 by Yaping Liu, Dongzhu Duan, Juan Yao, Baoxin Zhang, Shoujiao Peng, HuiLong Ma, Yanlin Song, Jianguo Fang
Any type of content formally published in an academic journal, usually following a peer-review process.
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.