Clinical Cancer Research, Vol 3, Issue 10 1679-1683, Copyright © 1997 by American Association for Cancer Research

ARTICLES

Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression

DJ Elder, DE Halton, A Hague and C Paraskeva
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandin H2. The inducible isoform, COX-2, promotes colorectal tumorigenesis, and nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit this isoform are chemopreventive in murine models of intestinal tumorigenesis. To establish a mechanism for their chemopreventive properties, we examined the effect of a COX-2-selective inhibitor, NS-398, on two colorectal carcinoma cell lines: HT29, which was found to express COX-2 protein constitutively; and S/KS, which did not express detectable levels of COX-2 protein. NS-398 had a dose-dependent antiproliferative effect on each cell line (IC50, 82.0 +/- 10.1 microM for HT29 and 78.6 +/- 11.1 microM for S/KS), and this was due to the induction of apoptosis. Cell cycle parameters were unaffected by NS-398 treatment. The ability of NS-398 to induce apoptosis provides a potential mechanism by which COX-2-selective inhibitors are chemopreventive and also indicates their potential as chemotherapeutic agents for colorectal cancer. That this effect was independent of COX-2 protein expression suggests that COX-2-selective NSAIDs may, like nonselective NSAIDs, be antineoplastic in the absence of COX-2.

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