The Study of Anticancer Mechanisms of WRC-213 and Mana-Hox in Human Prostate Cancer Cell Lines
| Autor: | Che-Jen Hsiao, 蕭哲仁 |
|---|---|
| Rok vydání: | 2008 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 96 In the present studies, we elucidate the anticancer mechanism of WRC-213 and Mana-Hox in the androgen-refractory human prostate adenicarcinoma PC-3 cells. In the first part, the research is to investigate the apoptotic mechanism of WRC-213, an anthracenedione derivative, in human prostate cancer PC-3 cells. WRC-213 induced apoptotic cell death in PC-3 cells in a concentration- and time-dependent manner. WRC-213 induced DNA damage and inhibited activity of topoisomerase II, resulting in cell cycle arrest at S and G2 phase. After the checkpoint arrest, WRC-213 induced mitochondrial-mediated intrinsic apoptotic pathway, including caspase-3/caspase-9 activation, Mcl-1 cleavage and Bcl-2 down-regulation. Survivin degradation and caspase-2 activation also contributed to WRC-213-induced apoptosis. Furthermore, the measurement of cytotoxicity in H9c2 cardiomyocytes and drug resistance in NCI/ADR-RES cells demonstrated that WRC-213 showed much lower cardiotoxicity and P-glycoprotein-related resistance than those of mitoxantrone, etoposide and doxorubicin. In conclusion, WRC-213 is a promising topoisomerase II poison for treatment of androgen-refractory human prostate adenocarcinoma. In the second part, the research is to investigate the apoptotic mechanism of Mana-Hox, a β-carbolin derivative, in human prostate cancer PC-3 cells. The data from flow cytometric analysis showed that Mana-Hox induced the accumulation of cells at G2/M phase and hypodiploid subG1 phase of the cell cycle. Tubulin assembly and Western blotting assays indicated that Mana-Hox induced tubulin depolymerization and DNA damage. Additionally, Mana-Hox induced up-regulation of cyclin B, down-regulation of cyclin A and cyclin E protein levels, and a marked increase of MPM-2 expression, suggesting the mitotic arrest to Mana-Hox action. Mana-Hox induced the activation of mitochondria-mediated apoptosis pathways and caused phosphorylation of Bcl-2, cleavage of Mcl-1 and PARP, and activation of caspase-3. Moreover, Mana-Hox showed much lower P-glycoprotein-related resistance than taxol, vincristine, etoposide, and doxorubicin. The data suggest that Mana-Hox is a potential compound for the development of prostate cancer chemotherapy. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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