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-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).
Cai
Yi
Y
George H. Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Lee
Yi-Fen
YF
Li
Gonghui
G
Liu
Su
S
Bao
Bo-Ying
BY
Huang
Jiaoti
J
Hsu
Cheng-Lung
CL
Chang
Chawnshang
C
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D005485:Flutamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D009578:Nitrobenzenes; D011944:Receptors, Androgen; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C014290:hydroxyflutamide; D005485:Flutamide; D051546:Cyclooxygenase 2