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- Title
A new prostate cancer therapeutic approach: Combination of androgen ablation with COX-2 inhibitor.
- Authors
Cai, Yi; Lee, Yi-Fen; Li, Gonghui; Liu, Su; Bao, Bo-Ying; Huang, Jiaoti; Hsu, Cheng-Lung; Chang, Chawnshang
- Abstract
Prostate cancer is initially responsive to hormonal therapy, but cancers inevitably progress in an androgen-independent fashion with virtually all tumors evolving into more aggressive androgen refractory disease. Immunohistological comparisons of cyclooxygenase 2 (COX-2) expressions in 3 pairs of prostate cancer patients before and after the combined androgen blockade (CAB) therapy show elevated COX-2 expressions. This observation from clinical specimens is further supported by in vitro laboratory data using human prostate cancer cells in which the antiandrogen hydroxyflutamide (HF) induced COX-2 expression, and androgen suppressed COX-2 expression. By applying knockdown and overexpression strategies to modulate AR expression in prostate cancer cells, we confirmed that androgen/AR signal suppressed, and HF induced COX-2 expression at both protein and mRNA levels. COX-2 promoter reporter assay indicated that the suppression of COX-2 by androgen/AR is at the transcriptional level via modulation of NF-κB signals. Treatment of LNCaP and LAPC4 cells with 1 μM HF in the presence of 1 nM DHT, which mimics the CAB therapy condition, promotes cell growth, and this growth induction can be suppressed via adding the COX-2 specific inhibitor, NS398. This suggests that HF promoted prostate cancer cell growth is COX-2 dependent and this HF-COX-2 activation pathway can account for one reason of CAB therapy failure. Together, these findings provide a possible explanation how CAB with antiandrogen HF therapy might fail and provide a potential new therapeutic approach to battle prostate cancer via combination of CAB therapy with COX-2 inhibitor(s). © 2008 Wiley-Liss, Inc.
- Publication
International Journal of Cancer, 2008, Vol 123, Issue 1, p195
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.23481