https://scholars.lib.ntu.edu.tw/handle/123456789/564796
標題: | A novel hydroxysuberamide derivative potentiates MG132-mediated anticancer activity against human hormone refractory prostate cancers - The role of histone deacetylase and endoplasmic reticulum stress | 作者: | Chen Y.-C. Huang W.-J. Hsu J.-L. Yu C.-C. Wang W.-T. JIH-HWA GUH |
關鍵字: | DNA repair; GADD153; HDAC inhibitor; intrinsic and extrinsic apoptosis pathways; proteasome inhibitor | 公開日期: | 2013 | 卷: | 73 | 期: | 12 | 起(迄)頁: | 1270-1280 | 來源出版物: | Prostate | 摘要: | BACKGROUND Histone deacetylase (HDAC) inhibitors are successful for treatment of advanced cutaneous T-cell lymphoma but only show modest effect in solid tumors. Approaches for HDAC inhibitors to improve activity against solid tumors are necessary. 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. Copyright ? 2013 Wiley Periodicals, Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84881069615&doi=10.1002%2fpros.22641&partnerID=40&md5=8bca249b7aa429b451f59326b50588c2 https://scholars.lib.ntu.edu.tw/handle/123456789/564796 |
ISSN: | 2704137 | DOI: | 10.1002/pros.22641 | SDG/關鍵字: | antineoplastic agent; benzyloxycarbonylleucylleucylleucinal; camptothecin; caspase 3; caspase 8; caspase 9; cyclin A; cyclin B1; cyclin D1; cyclin E; doxorubicin; etoposide; growth arrest and DNA damage inducible protein 153; histone deacetylase; histone deacetylase 1; histone deacetylase 2; histone deacetylase 4; histone deacetylase 6; histone deacetylase inhibitor; histone H3; Ku antigen; paclitaxel; protein bcl 2; protein p21; small interfering RNA; sulforhodamine B; unclassified drug; vincristine; vorinostat; wj 25591; antineoplastic activity; apoptosis; article; binding affinity; castration resistant prostate cancer; cell cycle progression; cell proliferation; comet assay; controlled study; DNA binding; DNA damage; DNA repair; DNA replication; DNA synthesis; down regulation; endoplasmic reticulum stress; flow cytometry; G1 phase cell cycle checkpoint; G2 phase cell cycle checkpoint; gene silencing; human; human cell; male; priority journal; protein expression; signal transduction; upregulation; Western blotting; DNA repair; GADD153; HDAC inhibitor; intrinsic and extrinsic apoptosis pathways; proteasome inhibitor; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leupeptins; Male; Prostatic Neoplasms; Proteasome Inhibitors |
顯示於: | 藥學系 |
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