Abstract
Thioredoxin reductase (TrxR) is overpressed in many human tumors and has a key role in regulating intracellular redox balance. Recently, thioredoxin system has emerged as a valuable target for anticancer drug development. Herein we demonstrate that selenocystine (SeC) could enhance auranofin (AF)-induced A549 human lung adenocarcinoma cell apoptosis in vitro and in vivo through synergetic inhibition of TrxR1. SeC pretreatment significantly enhanced AF-induced loss of mitochondrial membrane potential (Δψm) by regulating Bcl-2 family proteins. The combined treatment with SeC and AF also resulted in enhanced intracellular reactive oxygen species (ROS) accumulation, DNA damage, and inactivation of ERK and AKT. Inhibitors of ERK and AKT effectively enhanced combined treatment-induced apoptotic cell death. However, inhibition of ROS reversed the apoptosis induced by SeC and AF, and recovered the inactivation of ERK and AKT, which revealed the importance of ROS in cell apoptosis and regulation of ERK and AKT pathways. Moreover, xenograft lung tumor growth in nude mice was more effectively inhibited by combined treatment with SeC and AF by induction of apoptosis through targeting TrxR1 in vivo. Taken together, our results suggest the strategy to use SeC and AF in combination could be a highly efficient way to achieve anticancer synergism by targeting TrxR1.
Highlights
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases.[4]
We evaluated the ability of SeC to enhance AF-induced A549 human lung adenocarcinoma cell killing in vitro and in vivo
This study indicates that our strategy to use SeC and AF in combination could be a highly efficient way to achieve anticancer synergism by synergetic inhibition of TrxR1
Summary
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases.[4]. In the form of selenocysteine, has an essential part in several important redox enzymes, such as glutathione peroxidase and TrxR.[5] Selenocystine (SeC), a naturally available selenoamino acid, displays broad-spectrum anticancer activities in our previous studies. SeC-induced antiproliferative effect against human cancer cells involves oxidative stress-induced apoptosis, than that of selenomethionine, Se-methyl-seleno-cysteine, selenite, and selenate.[10] Despite this potency, SeC showed less toxic to human normal cells, indicating that SeC possesses great selectivity between human cancer and normal cells and displays potential application in cancer chemoprevention.[10] SeC shows potential therapeutic effect in vivo in inhibition of A375 melanoma cells through induction of apoptosis.[11]. We evaluated the ability of SeC to enhance AF-induced A549 human lung adenocarcinoma cell killing in vitro and in vivo. This study indicates that our strategy to use SeC and AF in combination could be a highly efficient way to achieve anticancer synergism by synergetic inhibition of TrxR1
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