title: Oridonin induces apoptosis and senescence by increasing hydrogen peroxide             and glutathione depletion in colorectal cancer cells.
abstract: We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated β-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.
authors.affiliation: Number 3 People's Hospital, Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 201900, PR China.
authors.forename: Feng-Hou
authors.initials: FH
authors.lastname: Gao
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: Liu
authors.forename: Mang-Hua
authors.initials: MH
authors.lastname: Xu
authors.forename: Zhu-Ying
authors.initials: ZY
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D017304:Annexin A5; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D045786:Diterpenes, Kaurane; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C011959:oridonin; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase; D001616:beta-Galactosidase; D005978:Glutathione; D000111:Acetylcysteine