Celecoxib Inhibits Prostate Cancer Growth: Evidence of a Cyclooxygenase-2-Independent Mechanism

Abstract

Purpose: 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.Experimental Design: 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 Mmol/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 dosedependent 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 Mmol/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 f50% 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.

Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation

“…However, no consensus exists concerning the underlying molecular mechanisms of these effects. Consistent with previous studies [36,45,46] , our results demonstrated that celecoxib induced G 0 /G 1 cell cycle arrest in HNE1 and CNE1-LMP1 cell lines and that this arrest was accompanied by the down-regulation of Cyclin D1 [12,[45][46][47] , which is one of the major cyclins known to be upregulated in cancers. Cyclin D1 activates Cyclin Dependent Kinase 2 (CDK2) and CDK4, leading to the phosphorylation of the retinoblastoma protein (pRb), which forces its release from the E2F transcription factor.…”

Cyclooxygenase inhibitors in urinary bladder cancer:in vitroandin vivoeffects

“…It is possible that greater antitumor activity and possibly tumor regression would occur with longer COX inhibitor treatment in mice. In mice with human prostate cancer xenografts, celecoxib caused much more dramatic antitumor effects after 25 days of treatment than after 14 days of treatment (19). In dogs with TCC who have tumor remission with COX inhibitor treatment, tumor regression is observed after f4 weeks of treatment and lifelong COX inhibitor therapy seems necessary.…”

Proteomic Profiling Identifies Cyclooxygenase-2-Independent Global Proteomic Changes by Celecoxib in Colorectal Cancer Cells

“…First, celecoxib has been shown to inhibit growth of cell lines that are deficient for COX-2 expression (12,13). Second, treatment with celecoxib resulted in growth inhibition of xenografts of COX-2-deficient colorectal and prostate cancer cell lines in nude mice (8,14). Third, concentration of celecoxib needed for growth inhibition in vitro is several orders of magnitude higher than the concentration at which COX-2 is inhibited (15,16).…”