期刊
JOURNAL OF UROLOGY
卷 185, 期 6, 页码 2376-2381出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.juro.2011.02.016
关键词
prostate; prostatic neoplasms; docetaxel; drug resistance, neoplasm; androgen antagonists
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Keio University
- Prostate Research Fund in Japan
- Grants-in-Aid for Scientific Research [22591777] Funding Source: KAKEN
Purpose: There are still few effective therapeutic options for advanced prostate cancer. One of the most troublesome aspects of prostate cancer is that androgen dependent prostate cancer inevitably progresses to highly aggressive, life threatening castration resistant prostate cancer after androgen ablation therapy. To our knowledge it remains unknown how sensitivity to docetaxel changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. Materials and Methods: We investigated sensitivity to docetaxel and phosphorylated Akt status in C4-2 and C4-2AT6 cells established at our institution. Results: C4-2AT6 cells established under androgen ablation conditions for 6 months showed significantly higher resistance to docetaxel than C4-2 cells in vivo and in vitro. Resistance was accompanied by increased phosphorylated Akt. In C4-2AT6 cells phosphorylated Akt activity was significantly up-regulated by docetaxel in a dose dependent manner. After treatment with docetaxel and a phosphatidylinositol 3-kinase/Akt inhibitor the sensitivity of C4-2AT6 cells to docetaxel markedly increased through enhanced apoptotic death. Conclusions: Findings indicated that up-regulation of phosphorylated Akt during androgen ablation and its further activation by docetaxel explains at least in part the resistance to docetaxel and progression to castration resistant prostate cancer under androgen ablation conditions.
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