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Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio

Requests for reprints: Ching-Shih Chen, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, 336 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210-1291. Phone: 614-688-4008; Fax: 614-688-8556. E-mail: chen.844{at}osu.edu

Evidence suggests that the angiogenic endothelium represents an important target through which celecoxib mediates in vivo antitumor effects. Nevertheless, the pharmacologic basis for celecoxib-caused growth inhibition in endothelial cells in vitro remains to be defined. Previously, we showed that celecoxib-induced apoptosis in PC-3 prostate cancer cells was mediated in part through the inhibition of 3-phosphoinositide-dependent kinase-1/Akt signaling. Our present findings show that celecoxib inhibits the growth of human umbilical vein endothelial cells (HUVEC) with pharmacologic profiles reminiscent of those of PC-3 cells. The underlying antiproliferative mechanism, however, may differ between these two cell types considering differences in the functional status of many tumor suppressors, including PTEN, p53, and retinoblastoma, all of which play integral roles in regulating cell cycle progression and survival. From a mechanistic perspective, the genomic integrity of the HUVEC system presents a vastly different intracellular context to examine how celecoxib acts to induce growth inhibition. Here, we obtain evidence that the antiproliferative effects of celecoxib and its close, cyclooxygenase-2-inactive analogue 4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (DMC) in HUVECs at pharmacologically attainable concentrations (10–20 µmol/L) are attributable to the inhibition of phosphoinositide-dependent kinase-1/Akt signaling and cyclin-dependent kinase. Especially, celecoxib- and DMC-mediated G₁ arrest is associated with attenuated retinoblastoma phosphorylation through the inhibition of multiple cyclin-dependent kinases (IC₅₀, 10–35 µmol/L). Moreover, both celecoxib and DMC reduce neovascularization in the chicken chorioallantoic membrane assay, suggesting the involvement of a cyclooxygenase-2-independent mechanism in the in vivo antiangiogenic effects of celecoxib.

Key Words: Celecoxib • HUVEC • Cell cycle arrest • Phosphoinositide-dependent kinase-1 • Cyclin-dependent kinases • 07-02-00 Mechanisms of drug action/new molecular targets/therapeutics • 07-02-01 Cell cycle mechanisms of anticancer drugs • 07-02-02 Cellular responses to anticancer drugs • 07-05-09 Kinase and phosphatase inhibitors

Grant support: NIH grant CA-94829.

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.

¹ http://dtp.nci.nih.gov/aa-resources/aa_index.html.

Received 5/ 5/04; revised 9/ 3/04; accepted 10/18/04.