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Research Articles: Therapeutics, Targets, and Development

Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells

Departments of ¹ Basic Medical Sciences and ² Veterinary Clinical Sciences, ³ Purdue Cancer Center, and ⁴ Purdue Oncological Sciences Center, Purdue University, West Lafayette, Indiana

Requests for reprints: Deborah W. Knapp, Department of Veterinary Clinical Sciences, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026. Phone: 765-494-9900. E-mail: knappd{at}purdue.edu

Abstract

Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)–coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (5 µmol/L) inhibited proliferation of COX-2–expressing HT1376 cells in soft agar and modified monolayer cell culture conditions in a COX-2–dependent manner. COX-2 expression, however, did not always correlate with response to celecoxib. TCCSUP cells that express COX-2 were minimally affected by celecoxib, and UMUC3 cells that lack COX-2 expression were modestly inhibited by the drug. When UMUC3^Cox-2/Tet cells overexpressing COX-2 under the control of tetracycline-inducible promoter were treated with celecoxib in modified monolayer cell culture, growth inhibition was found to be associated with changes in the expression of pRb. Not surprisingly, the proliferation of all cell lines was inhibited by excessively high concentrations of celecoxib. In conclusion, the modified culture conditions allowed detection of COX-2–dependent and COX-2–independent growth-inhibitory activity of celecoxib in urinary bladder cancer cells. [Mol Cancer Ther 2008;7(4):897–904]

Grant support: USPHS-NIH grant R21 CA093011.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ S.I. Mohammed, D.W. Knapp, unpublished data.

⁶ A.J. Dannenberg, personal communication.

Received 5/ 4/07; revised 2/ 5/08; accepted 3/ 4/08.