Abstract
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. 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. 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. 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.
Highlights
Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2 ^ independent mechanism(s); the toxicity issue is a concern with single agents at higher doses
The results presented in this study clearly show a novel but diverse mode of action by celecoxib in combination with exisulind against MNU/testosterone-induced prostate cancer
The overall tumor growth inhibition detected by apoptosis in rats given with celecoxib in combination with exisulind is orchestrated by a novel interaction between four independent mechanisms primarily targeting inflammation, cell cycle, androgen receptor (AR) regulation, and epidermal growth factor receptor (EGFR) signal transduction pathways
Summary
Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2 ^ independent mechanism(s); the toxicity issue is a concern with single agents at higher doses. We used a Wistar-Unilever rat model in which prostate cancer was induced by a sequential regimen of N-methyl-N-nitrosourea (MNU) + testosterone [36, 37] Using this model, we have shown for the first time that the combination of a COX-2 inhibitor, celecoxib, with a cyclic GMP phosphodiesterase inhibitor, exisulind (sulindac sulfone/ Aptosyn), is more effective in preventing prostate cancer growth. We have shown for the first time that the combination of a COX-2 inhibitor, celecoxib, with a cyclic GMP phosphodiesterase inhibitor, exisulind (sulindac sulfone/ Aptosyn), is more effective in preventing prostate cancer growth To our knowledge, this is the first report on the use of a low-dose combination of celecoxib with exisulind in preventing carcinogen-induced prostate cancer in a preclinical model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
