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

• Published in: Clinical cancer research Vol. 3; no. 10; pp. 1679 - 1683
• Main Authors: ELDER, D. J. E, HALTON, D. E, HAGUE, A, PARASKEVA, C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.1997
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Division - drug effects; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; General aspects; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - physiology; Medical sciences; Membrane Proteins; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - physiology; Nitrobenzenes - pharmacology; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - physiology; Rectal Neoplasms - enzymology; Rectal Neoplasms - pathology; Sulfonamides - pharmacology; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Prostaglandin-endoperoxide synthase; Rectal disease; Carcinoma; Prevention; Cell cycle; Established cell line; Intestinal disease; Colon; Mechanism of action; Tumor cell; Human; Enzyme; Induction; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Colonic disease; Non steroidal antiinflammatory agent; Cell death; Rectum; Digestive diseases; Oxidoreductases; Apoptosis
• ISSN: 1078-0432; 1557-3265

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.