期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 12, 页码 5203-5211出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500221p
关键词
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资金
- National Natural Science Foundation of China [21002047, J1103307]
- Ministry of Education of China [20100211110027]
- Lanzhou University (Fundamental Research Funds for the Central Universities) [lzujbky-2014-56]
- 111 Project
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.
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