The metabolism of the R and S epimers of sulindac and their ability to enhance the selective killing of cancer cells by oxidative stress

Abstract

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.