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Mechanism of apicidin-induced cell cycle arrest and apoptosis in Ishikawa human endometrial cancer cells.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2009 May 15; Vol. 179 (2-3), pp. 169-77. Date of Electronic Publication: 2008 Nov 25. - Publication Year :
- 2009
-
Abstract
- Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer agents that act by inhibiting cell proliferation and inducing apoptosis in a variety of cancer cells. Although apicidin acts as a potent HDAC inhibitor, the precise mechanism for its anti-tumor activity in human endometrial cancer cells is not completely understood. This study examined the anti-tumor effects of apicidin in Ishikawa cancer cells. The level of cell proliferation, the stage of the cell cycle, and apoptosis were measured after the apicidin treatment. Apicidin significantly inhibited the proliferation of Ishikawa cells in a dose-dependent manner. In addition, apicidin markedly up-regulated the p21(WAF1) and down-regulated the expression of cyclins (A, B1, D1, or E), and CDKs (2 or 4), which leading to cell cycle arrest. Cell cycle analysis showed that the apicidin treatment increased the proportion of cells in the G1 phase, and decreased the ratio of cells in the S phase in a dose-dependent manner. Apicidin significantly increased the sub-G1 population and the number of TUNEL positive apoptotic cells compared with the untreated control. These results were confirmed by poly-ADP ribose polymerase (PARP), an 85-kDa fragment resulting from PARP cleavage, where apicidin increased the level of PARP cleavage and caspase-3 activity in 1.0 microM apicidin-treated cells. Apicidin-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and the decrease in the Bax/Bcl-2 ratio. These results suggest that apicidin has anti-tumor properties on endometrial cancer cells by inducing selectively the genes related to cell cycle arrest and apoptosis.
- Subjects :
- Blotting, Western
Caspase 3 metabolism
Cell Proliferation drug effects
Cyclin-Dependent Kinase Inhibitor p21 genetics
Cyclin-Dependent Kinases biosynthesis
Cyclin-Dependent Kinases genetics
Cyclins biosynthesis
Cyclins genetics
Cytochromes c metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
G1 Phase drug effects
Gene Expression Regulation, Neoplastic drug effects
Histones metabolism
Humans
Proto-Oncogene Proteins c-bcl-2 drug effects
Proto-Oncogene Proteins c-bcl-2 genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Apoptosis drug effects
Cell Cycle drug effects
Endometrial Neoplasms pathology
Peptides, Cyclic pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 179
- Issue :
- 2-3
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 19070610
- Full Text :
- https://doi.org/10.1016/j.cbi.2008.11.011