Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence.

Abstract

PURPOSE:

Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer.

EXPERIMENTAL DESIGN:

We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays.

RESULTS:

The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination.

CONCLUSIONS:

In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.

• Authors: Bhagavathi A Narayanan, Bandaru S Reddy, Maarten C Bosland, Dominick Nargi, Lori Horton, Carla Randolph, Narayanan K Narayanan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 19 Pg. 5965-73 (Oct 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17908994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticarcinogenic Agents
• Cyclooxygenase Inhibitors
• Pyrazoles
• Receptors, Androgen
• Sulfonamides
• Cyclin D1
• Sulindac
• Testosterone
• Methylnitrosourea
• Cyclooxygenase 2
• ErbB Receptors
• Celecoxib
• sulindac sulfone

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Celecoxib
• Cyclin D1 (biosynthesis)
• Cyclooxygenase 2 (biosynthesis)
• Cyclooxygenase Inhibitors (administration & dosage)
• ErbB Receptors (biosynthesis)
• Humans
• Male
• Methylnitrosourea (pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism)
• Pyrazoles (administration & dosage)
• Rats
• Rats, Wistar
• Receptors, Androgen (metabolism)
• Sulfonamides (administration & dosage)
• Sulindac (administration & dosage, analogs & derivatives)
• Testosterone (pharmacology)