A new prostate cancer therapeutic approach: Combination of androgen ablation with COX‐2 inhibitor

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.