BackgroundSulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID) that affects prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2. Sulindac has also been of interest for more than decade as a chemopreventive for adenomatous colorectal polyps and colon cancer.Principal FindingsPretreatment of human colon and lung cancer cells with sulindac enhances killing by an oxidizing agent such as tert-butyl hydroperoxide (TBHP) or hydrogen peroxide. This effect does not involve cyclooxygenase (COX) inhibition. However, under the conditions used, there is a significant increase in reactive oxygen species (ROS) within the cancer cells and a loss of mitochondrial membrane potential, suggesting that cell death is due to apoptosis, which was confirmed by Tunel assay. In contrast, this enhanced killing was not observed with normal lung or colon cells.SignificanceThese results indicate that normal and cancer cells handle oxidative stress in different ways and sulindac can enhance this difference. The combination of sulindac and an oxidizing agent could have therapeutic value.

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Sulindac is a non‐steroidal anti‐inflammatory (NSAID) prodrug which requires reduction to sulindac sulfide in order to become an active cyclooxygenase (COX) inhibitor. Recent studies have demonstrated that sulindac and its derivatives have anti‐cancer activity, although the mechanism remains unknown. Sulindac has a chiral sulfur center and exists as R and S epimers. We have isolated the individual epimers and found that both have similar activity against human colon, lung and skin cancer cell lines, providing enhanced killing in the presence of the oxidizing agent tert‐butylhydroperoxide (TBHP), while not adversely affecting normal cells. The death of the cells is accompanied by loss of mitochondrial membrane potential, indicating an apoptotic pathway. Previous in vitro enzymatic studies have indicated that methionine sulfoxide reductase A (MsrA) can reduce the S epimer. In the current studies with whole cells, we have observed that the S epimer was much more rapidly reduced than the R epimer in normal cells, while in cancer cell lines the reduction of both epimers occurred at similar rates. These results suggest that the R epimer may have a higher safety profile when used in the treatment of human cancers, as it is not as rapidly converted to a COX inhibitor in normal cells. Studies are ongoing to elucidate the enzymes and tissue‐specific conditions responsible for the differential metabolism of the R and S epimers.

Sulindac can be oxidized to sulindac sulfone and reduced to sulindac sulfide, an active cyclooxygenase (COX) inhibitor. However, the metabolism and biological activities of the individual R and S epimers are not known. In vivo, the R epimer yielded higher plasma levels of the sulfone, whereas the S epimer was more readily reduced to the sulfide. In a hepatoma cell line, both epimers activated the aryl hydrocarbon receptor and significantly induced cytochrome P450 enzymes. The R epimer was oxidized to sulindac sulfone more readily than the S epimer. A rat liver cell extract reduced both the R and S epimers of sulindac with either DTT or thioredoxin. The S epimer is primarily reduced by methionine sulfoxide reductase A (MsrA). The enzyme(s) responsible for reduction of the R epimer has been partially purified.Sulindac enhances killing of human colon, skin, and lung cancer cells by oxidative stress. The effect does not involve COX inhibition or the Msr system. An increase in reactive oxygen species (ROS) and loss of mitochondrial membrane potential suggest that cell death is due to apoptosis. Both epimers were effective under the conditions used. In contrast, no enhanced killing was observed using either epimer with normal cells under the same conditions. In summary it appears that the R and S epimers of sulindac are metabolized by different pathways and that these epimers may have different pharmacological properties.