SULFONE METABOLITE OF SULINDAC INHIBITS MAMMARY CARCINOGENESIS

Sulindac sulfoxide, a commonly prescribed anti-inflammatory drug, has cancer chemopreventive activity, During its metabolism, the inactive p rodrug sulindac sulfoxide undergoes either reduction to the active ant iinflammatory metabolite sulindac sulfide or irreversible oxidation to sulindac sulfone, which lacks prostaglandin synthetase inhibitory act ivity, Interestingly, sulindac sulfone has been reported to have cance r chemopreventive activity, The objective of the experiments reported here was to investigate the chemopreventive activity of sulindac sulfo ne against mammary carcinogenesis and to study its mechanism, Rats wer e injected with either 12.5 or 37.5 mg of 1-methyl-1-nitrosourea (MNU) /kg body weight at 50 days of age, Sulindac sulfone was incorporated i nto a purified diet at a concentration of either 0.03 or 0.06% (w/w) a nd fed to rats beginning 7 days after the injection of MNU, Sulindac s ulfoxide at a level of 0.06% (w/w) was fed as a reference for comparis on, Thirty rats were assigned to each dietary group treated with the h igh dose of MNU, and 44 rats were assigned to each dietary group treat ed with the low dose of MNU, The sulfone reduced cancer incidence and the number of cancers per rat irrespective of the dose of MNU injected , and its chemopreventive activity was comparable to that of sulindac sulfoxide. Cancer latency was also prolonged significantly by sulindac sulfone; the effect was particularly notable at the low dose of carci nogen, at which the prolongation of latency was >8 weeks, The sulfone inhibited the occurrence of mammary carcinomas that were classified as having either a wild-type or a mutant codon 12 in the Ha-ras gene; ho wever, the inhibitory effect was greater against carcinomas with a mut ant Ha-ras genotype, Using a mammary gland organ culture transformatio n assay, it was observed that sulindac sulfone also inhibited the form ation of 7,12-dimethylbenz(a)anthracene-induced hyperplastic alveolar nodules and that the inhibitory activity of the sulfone was comparable to that of the sulfoxide. These data indicate that the observed effec t of the sulfone on mammary carcinogenesis in vivo is likely to be due to a tissue-specific effect rather than to other systemic effects, Th e findings that both the prodrug and the sulfone inhibited carcinogene sis in vivo and nodule formation in organ culture and that the sulfone lacks inhibitory activity on prostaglandin synthesis suggest a mechan ism(s) of chemoprevention that is independent of the prostaglandin pat hway, A candidate mechanism for the apparent clonal selection pressure exerted by the sulfone against mammary carcinogenesis is apoptosis, T o test this hypothesis, MCF-7 cells were exposed to a range of concent rations of sulindac sulfone and sulfoxide, Both compounds inhibited ce ll growth and induced apoptosis in the absence of necrosis, Collective ly, these data support a specific chemopreventive effect of sulindac s ulfone against mammary carcinogenesis and indicate that this compound may have a selective effect against carcinogenesis involving alteratio ns in the signal transduction cascade of which Ha-ras is a component E vidence is consistent with the involvement of apoptosis in the cancer- inhibitory activity observed.