Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo.
Thioredoxin reductase (TrxR) is overexpressed 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.
Department of Chemistry, Jinan University, Guangzhou, China.
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Fan
Department of Chemistry, Jinan University, Guangzhou, China.
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Zheng
Department of Chemistry, Jinan University, Guangzhou, China.
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Fu
Department of Chemistry, Jinan University, Guangzhou, China.
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Li
School of Life Sciences and State Key Laboratory of Agrobiotechnology, Chinese University of Hong Kong, Hong Kong, China.
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Wong
Department of Chemistry, Jinan University, Guangzhou, China.
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Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D016566:Organoselenium Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D016566:Organoselenium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C009226:selenocystine; D001310:Auranofin; D003553:Cystine; D054481:Thioredoxin Reductase 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases