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Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells.
- Source :
-
International journal of molecular medicine [Int J Mol Med] 2012 Apr; Vol. 29 (4), pp. 649-55. Date of Electronic Publication: 2012 Jan 24. - Publication Year :
- 2012
-
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.
- Subjects :
- Acetylcysteine pharmacology
Annexin A5 metabolism
Cell Line, Tumor
Cellular Senescence
Colorectal Neoplasms pathology
Cyclin-Dependent Kinase Inhibitor p16
Down-Regulation
Humans
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Proto-Oncogene Proteins c-myc genetics
Proto-Oncogene Proteins c-myc metabolism
Reactive Oxygen Species metabolism
Thioredoxin-Disulfide Reductase antagonists & inhibitors
Thioredoxin-Disulfide Reductase drug effects
Thioredoxin-Disulfide Reductase metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Up-Regulation
beta-Galactosidase metabolism
Apoptosis drug effects
Diterpenes, Kaurane pharmacology
Glutathione metabolism
Hydrogen Peroxide metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1791-244X
- Volume :
- 29
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 22294162
- Full Text :
- https://doi.org/10.3892/ijmm.2012.895