Abstract | BACKGROUND: METHODS:
Sulforhodamine B assay and flow cytometric analysis detected cell proliferation and cell-cycle progression, respectively. Protein expression was determined by Western blotting. Comet assay and DNA end-binding activity of Ku proteins detected DNA damage and DNA repair activity, respectively. siRNA technique was used for knockdown of specific cellular target. RESULTS: WJ25591 displayed inhibitory activity against HDAC1 and cell proliferation in human hormone-refractory prostate cancers PC-3 and DU-145. WJ25591 caused an arrest of cell-cycle at both G1- and G2-phase and increased protein expressions of p21 and cyclin E, followed by cell apoptosis. WJ25591-induced Bcl-2 down-regulation and activation of caspase-9, -8, and -3, suggesting apoptotic execution through both intrinsic and extrinsic apoptotic pathways. WJ25591 also significantly inhibited DNA repair activity but not directly induced DNA damage. Moreover, the proteasome inhibitor MG-132 dramatically sensitized WJ25591-induced cell apoptosis. The siRNA technique demonstrated that endoplasmic reticulum (ER) stress, in particular CHOP/GADD153 up-regulation, contributed to the synergistic effect. CONCLUSIONS: The data suggest that WJ25591 inhibited HDAC activity, leading to cell-cycle arrest and inhibition of DNA repair. Caspase cascades are subsequently triggered to execute cell apoptosis. MG-132 dramatically sensitizes WJ25591-mediated apoptosis, at least partly, through ER stress response. The data also reveal that combination of HDAC inhibitors and proteasome inhibitors may be a potential strategy against hormone-refractory prostate cancers.
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Authors | Yi-Cheng Chen, Wei-Jan Huang, Jui-Ling Hsu, Chia-Chun Yu, Wei-Ting Wang, Jih-Hwa Guh |
Journal | The Prostate
(Prostate)
Vol. 73
Issue 12
Pg. 1270-80
(Sep 2013)
ISSN: 1097-0045 [Electronic] United States |
PMID | 23813634
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Wiley Periodicals, Inc. |
Chemical References |
- Antineoplastic Agents
- Histone Deacetylase Inhibitors
- Leupeptins
- Proteasome Inhibitors
- Histone Deacetylases
- benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Topics |
- Antineoplastic Agents
(administration & dosage)
- Cell Cycle
(drug effects, physiology)
- Cell Line, Tumor
- Drug Synergism
- Endoplasmic Reticulum Stress
(drug effects, physiology)
- Histone Deacetylase Inhibitors
(administration & dosage)
- Histone Deacetylases
(physiology)
- Humans
- Leupeptins
(administration & dosage)
- Male
- Prostatic Neoplasms
(drug therapy, enzymology, physiopathology)
- Proteasome Inhibitors
(administration & dosage)
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