Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells

Abstract

Sulindac is a nonsteroidal antiinflammatory drug that has been demonstrated to be a potent chemopreventive agent against colorectal cancer in both human and animal models. In vivo, sulindac may be reversibly reduced to the active antiinflammatory compound, sulindac sulfide, or irreversibly oxidized to sulindac sulfone. Sulindac has also been shown to inhibit polycyclic aromatic hydrocarbon (PAH)-induced cancer, but the molecular mechanisms of its antitumor effect remain unclear. In this study, we investigated the effects of sulindac and its metabolites on the expression of enzymes that metabolize and detoxify PAHs in 2 human colon cancer cell lines, LS180 and Caco-2. Sulindac and sulindac sulfide induced a sustained, concentration-dependent increase in CYP enzyme activity as well as an increase in the mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Sulindac and sulindac sulfide induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear CYP1A1 RNA and verified by the use of actinomycin D as a transcription inhibitor. Chromatin immunoprecipitation assays demonstrated that sulindac and sulindac sulfide also increased the nuclear level of activated aryl hydrocarbon receptor, the transcription factor which mediates CYP expression. Additionally, sulindac and both metabolites increased the activity and mRNA expression of the carcinogen detoxification enzyme NAD(P)H:quinone oxidoreductase, as well as the expression of UDP-glucuronosyltransferase mRNA. These results show an overall upregulation of carcinogen metabolizing enzymes in colon cancer cells treated with sulindac, sulindac sulfide and sulindac sulfone that may contribute to the established chemoprotective effects of these compounds. ' 2007 Wiley-Liss, Inc.

CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers

“…Interestingly, it was found that AhR was a putative Wnt/ß-catenin target in prostate cancers (30). In addition, sulindac, one of the nonsteroidal anti-inflammatory drugs (NSAIDs), exerts its chemopreventive effects by inducing carcinogen metabolizing enzymes such as CYP1B1 through activating AhR (31). Therefore, aberrant expression of CYP1B1 by promoter methylation might play roles in colorectal carcinogenesis through Wnt/ß-catenin signaling pathway.…”

Two Novel Approaches Providing Cardiac Protection Against Oxidative Stress

“…The reduction of the S epimer is catalyzed by MsrA and as seen in Figure 6, the R epimer is reduced by an enzyme in liver that has the properties of MsrB (Brunell et al, 2011). Sulindac can also induce the P450 system and be oxidized by the P450 system to sulindac sulfone (Ciolino et al, 2008;Brunell et al, 2011). Sulindac sulfone is not an NSAID and is not a substrate for the Msr system.…”

Studies on the Metabolism and Biological Activity of the Epimers of Sulindac

“…Previous studies showed that sulindac could induce several of the P450 enzymes that were regulated by the AHR (Ciolino et al, 2006(Ciolino et al, , 2008. These authors used ethoxyresorufin as a substrate to measure induction of the P450 system but did not measure the induction of the P450 enzymes that oxidize sulindac or the effect of the sulindac FIG.…”

“…It should be noted that the R-epimer is oxidized at a faster rate than the S-epimer, regardless of which epimer is used during the preincubation (induction) period. We assume that the sulindac epimers are inducing the P450 enzymes in these experiments because Ciolino et al (2006Ciolino et al ( , 2008 have clearly shown that sulindac and its metabolites can induce several P450 enzymes. However, we should stress that we have not directly shown that the P450 enzymes are induced, only that there is an increase in P450 enzymatic activity after the cells are exposed to sulindac over a 24-h period.…”

“…It has been reported (Ciolino et al, 2006(Ciolino et al, , 2008 that sulindac induces some members of the microsomal P450 system via a mechanism involving the aryl hydrocarbon receptor (AHR), but the specific enzymes responsible for sulindac oxidation were not identified. No studies on the oxidation of the individual epimers of sulindac have been reported.…”