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


METHODS
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.
Narayanan
Bhagavathi A
BA
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA. bhagavathi@env.med.nyu.edu
Reddy
Bandaru S
BS
Bosland
Maarten C
MC
Nargi
Dominick
D
Horton
Lori
L
Randolph
Carla
C
Narayanan
Narayanan K
NK
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D019938:Cyclin D1 / Q000096:biosynthesis*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D066246:ErbB Receptors / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013739:Testosterone / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011944:Receptors, Androgen; D013449:Sulfonamides; D019938:Cyclin D1; D013467:Sulindac; D013739:Testosterone; D008770:Methylnitrosourea; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D000068579:Celecoxib; C025463:sulindac sulfone