The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective intreating intestinal adenomas in humans with Familial Adenomatous Polyposis(FAP) and in preventing intestinal tumors in the C57Bl/6J- Min+ (Min)mouse, an animal model of FAP. Sulindac is a prodrug metabolized by theliver and intestinal flora to a sulfone, which has no anti-inflammatoryactivity, and a sulfide, which is the active anti- inflammatory metabolite.In this study, we determined which of these metabolites is responsible forthe anti-tumor effect of sulindac in Min mice. Min mice were treated witheither sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min miceand homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation(+/+) were used as controls. At 110 days of age, all mice were euthanizedand their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindacsulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mousefor sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyteapoptosis was observed in Min control mice and Min mice treated withsulindac sulfone. Sulindac sulfide restored to normal the level ofapoptosis in the mucosa of Min animals and decreased levels of PGE2 in thesmall intestine of treated Min animals by 59% (P < 0.001). These datasuggest that the anti-tumor effect of sulindac in Apc-deficient animals ismediated by the sulfide metabolite and correlates with suppression oftissue prostaglandin synthesis.