Antiproliferative Effects of the Enantiomers of Flurbiprofen

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) are recognized for inhibiting growth of colon tumors in animal models, and for reducing the risk of colon cancer in humans. The mechanisms involved have not been established, but are thought to be related to reduced prostaglandin biosynthesis. The present study investigates the effect of COX-inhibiting and non-COX-inhibiting enantiomers of flurbiprofen on rat colonocyte proliferation. Intestinal ulceration was used as a surrogate indicator of COX inhibition. Sprague Dawley rats were treated orally with 6.3 mg/kg of R- or s-flurbiprofen or vehicle. Colonocyte labeling index and small bowel ulcer index were measured. R-flurbiprofen and S-flurbiprofen significantly reduced colonocyte labeling index, by 34% and 23% respectively, compared with vehicle. R-flurbiprofen caused minimal ulcer formation (4.48 mm2) compared with S-flurbiprofen (94.4 mm2). These findings suggest that R-flurbiprofen-mediated control of colonocyte proliferation is independent of prostaglandin biosynthesis.

The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64

“…Non-steroidal anti-in¯amma-tory drugs (NSAIDs) that target COX-2 have been shown to induce regression of Min adenomas independent of prostaglandin biosynthesis (Chiu et al, 1997;Moorghen et al, 1998;Mahmoud et al, 1998). NSAIDs can also inhibit the proliferation of human colon cancer cells (Hanif et al, 1996;Erickson et al, 1999;McCracken et al, 1996;Levy, 1997), as well as chemically induced colon tumors in rats (Reddy et al, 1999;Charalambous et al, 1998), independent of prostaglandins. Crucially, the molecular genetic studies reported in this paper and its predecessors provide strong evidence that Pla2g2a diminishes, rather than enhances, intestinal tumorigenesis in the mouse, particularly in the large intestine, where this eect is dosage-dependent.…”

Induction of cell growth arrest and apoptotic cell death in human breast cancer MCF-7 cells by the COX-1 inhibitor FR122047

“…However, several lines of evidence suggest that NSAIDs could also regulate signal pathways through COX-independent mechanisms. For example, NSAIDs lessened cell survival in COX-deficient cell lines such as HCT-15 colon cancer cell line and C33A cervical cancer cell line (28,29) and have also been reported to induce anti-inflammatory effects and apoptosis through various signaling pathways independently of COXs inhibition (30)(31)(32). FR122047, a COX-1 inhibitor induced apoptosis in MCF-7 breast cancer cells by a mechanism independent of its ability to suppress PGs synthesis because exogenous PGE 2 had no effect on FR122047-induced apoptosis in MCF-7 cells (data not shown).…”

Predominant Contribution of UDP-Glucuronosyltransferase 2B7 in the Glucuronidation of Racemic Flurbiprofen in the Human Liver

“…Although the anti-inflammatory activity is almost entirely attributable to (S)-flurbiprofen (Kulmacz and Lands, 1985), it has been suggested that both (R)-and (S)-flurbiprofen may possess antinociceptive activity (Brune et al, 1991;Geisslinger and Schaible, 1996). In addition, both enantiomers have been shown to exhibit antiproliferative effects (McCracken et al, 1996). Flurbiprofen exists as a chiral compound with a stereoselective disposition in humans (Geisslinger et al, 1994) and is metabolized via several drug metabolizing pathways, including cytochromes P450 and UDP-glucuronosyltransferases (UGTs).…”