Enhancement of auranofin-induced apoptosis in MCF-7 human breast cells by selenocystine, a synergistic inhibitor of thioredoxin reductase.
Thioredoxin system plays an important role in regulation of intracellular redox balance and various signaling pathways. Thioredoxin reductase (TrxR) is overexpressed in many cancer cells and has been identified as a potential target of anticancer drugs. Auranofin (AF) is potent TrxR inhibitor with novel in vitro and in vivo anticancer activities. Selenocystine (SeC) is a nutritionally available selenoamino acid with selective anticancer effects through induction of apoptosis. In the present study, we demonstrated the synergistic effects and the underlying molecular mechanisms of SeC in combination with AF on MCF-7 human breast cancer cells. The results showed that SeC and AF synergistically inhibited the cancer cell growth through induction of ROS-dependent apoptosis with the involvement of mitochondrial dysfunction. DNA damage-mediated p53 phosphorylation and down-regulation of phosphorylated AKT and ERK also contributed to cell apoptosis. Moreover, we demonstrated the important role of TrxR activity in the synergistic action of SeC and AF. 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 TrxR.
Department of Chemistry, Jinan University, Guangzhou, China.
Chaoran
C
Liu
Zhong
Z
Liu
Meng
M
Li
Xiaoling
X
Li
Yum-Shing
YS
Wong
Sai-Ming
SM
Ngai
Wenjie
W
Zheng
Yibo
Y
Zhang
Tianfeng
T
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004249:DNA Damage; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017279:Selenocysteine / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D017279:Selenocysteine; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases