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Exisulind in Combination with Celecoxib Modulates Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Cyclin D1 against Prostate Carcinogenesis: In vivo Evidence

Authors' Affiliations: ¹ Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York; ² Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey; and ³ Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Bhagavathi A. Narayanan, Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987. Phone: 845-731-3624; Fax: 845-351-4510; E-mail: bhagavathi{at}env.med.nyu.edu.

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- 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- indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr⁹⁹² and Tyr⁸⁴⁵) and Akt (Ser⁴⁷³) 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.