Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-i nflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has be en reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We stu died the effects of these sulindac metabolites in human colon cancer-derive d Caco-2 cells that have been transfected with an activated K-ras oncogene, Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more q uickly when injected into severe combined immunodeficiency disease mice tha n parental cells, and this tumorigenesis was suppressed by treatment with s ulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulte d in a decrease in prostaglandin synthase E-2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin sy nthase E-2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert CO X-dependant effects by distinct mechanisms.