Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism.
OBJECTIVE
Selective cyclooxygenase-2 (COX-2) inhibitors may suppress carcinogenesis by both COX-2-dependent and COX-2-independent mechanisms. The primary purpose of this study was to evaluate whether celecoxib or rofecoxib, two widely used selective COX-2 inhibitors, possess COX-2-independent antitumor activity.


METHODS
PC3 and LNCaP human prostate cancer cell lines were used to investigate the growth inhibitory effects of selective COX-2 inhibitors in vitro. To complement these studies, we evaluated the effect of celecoxib on the growth of PC3 xenografts.


RESULTS
COX-1 but not COX-2 was detected in PC3 and LNCaP cells. Clinically achievable concentrations (2.5-5.0 micromol/L) of celecoxib inhibited the growth of both cell lines in vitro, whereas rofecoxib had no effect over the same concentration range. Celecoxib inhibited cell growth by inducing a G(1) cell cycle block and reducing DNA synthesis. Treatment with celecoxib also led to dose-dependent inhibition of PC3 xenograft growth without causing a reduction in intratumor prostaglandin E(2). Inhibition of tumor growth occurred at concentrations (2.37-5.70 micromol/L) of celecoxib in plasma that were comparable with the concentrations required to inhibit cell growth in vitro. The highest dose of celecoxib led to a 52% reduction in tumor volume and an approximately 50% decrease in both cell proliferation and microvessel density. Treatment with celecoxib caused a marked decrease in amounts of cyclin D1 both in vitro and in vivo.


CONCLUSIONS
Two clinically available selective COX-2 inhibitors possess different COX-2-independent anticancer properties. The anticancer activity of celecoxib may reflect COX-2-independent in addition to COX-2-dependent effects.
Patel
Manish I
MI
Department of Medicine, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA.
Subbaramaiah
Kotha
K
Du
Baoheng
B
Chang
Mindy
M
Yang
Peiying
P
Newman
Robert A
RA
Cordon-Cardo
Carlos
C
Thaler
Howard T
HT
Dannenberg
Andrew J
AJ
D000818:Animals; D000068579:Celecoxib; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib