A new prostate cancer therapeutic approach: combination of androgen ablation with COX-2 inhibitor.

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-kappaB signals. Treatment of LNCaP and LAPC4 cells with 1 microM 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).

• Authors: Yi Cai, Yi-Fen Lee, Gonghui Li, Su Liu, Bo-Ying Bao, Jiaoti Huang, Cheng-Lung Hsu, Chawnshang Chang
• Journal: International journal of cancer (Int J Cancer) Vol. 123 Issue 1 Pg. 195-201 (Jul 01 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18386814 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Androgen Antagonists
• Androgens
• Antineoplastic Agents, Hormonal
• Cyclooxygenase 2 Inhibitors
• NF-kappa B
• Nitrobenzenes
• Receptors, Androgen
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• hydroxyflutamide
• Flutamide
• Cyclooxygenase 2

Topics

• Androgen Antagonists (therapeutic use)
• Androgens (metabolism)
• Antineoplastic Agents, Hormonal (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Blotting, Western
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (therapeutic use)
• Disease Progression
• Fluorescent Antibody Technique
• Flutamide (analogs & derivatives, therapeutic use)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Male
• NF-kappa B (metabolism)
• Nitrobenzenes (therapeutic use)
• Polymerase Chain Reaction
• Prostatic Neoplasms (drug therapy, enzymology)
• Receptors, Androgen (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfonamides (therapeutic use)
• Transfection
• Tumor Cells, Cultured
• Up-Regulation