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Cancer Therapy: Preclinical |
1 Department of Medicine, Weill Medical College of Cornell University; Departments of 2 Urology, 3 Epidemiology and Biostatistics, and 4 Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; 5 Department of Surgery, University of Sydney, Sydney, Australia; and 6 Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Andrew J. Dannenberg, New York Presbyterian-Cornell, 525 East 68th Street, Room F-206, New York, NY 10021. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.
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 µmol/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 G1 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 E2. Inhibition of tumor growth occurred at concentrations (2.37-5.70 µmol/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 
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.
Key Words: Cyclooxygenase-2 • prostaglandin • angiogenesis
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