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.