Sulindac regulates the aryl hydrocarbon receptor-mediated expression of Phase 1 metabolic enzymes in vivo and in vitro

Ciolino, Henry P.; MacDonald, Christopher J.; Memon, Omar; Bass, Sara; Yeh, Grace Chao

doi:10.1093/carcin/bgi359

Cited by 32 publications

(39 citation statements)

References 32 publications

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“…It has been shown to induce the expression of several P450 enzymes (39) and ubiquinone oxido/reductase, a marker for the Phase 2 system (40). Thus, the activity of sulindac as a chemoprotectant could involve a combination of activities, including antiinflammatory, cell preconditioning, and induction of Phase 1 and Phase 2 enzymes.…”

Section: Discussionmentioning

confidence: 99%

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Moench

Prentice

Rickaway³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We have recently shown that sulindac, an anti-inflammatory drug, enhances the killing of cancer cells, but not normal cells, under conditions of oxidative stress, by mechanisms unrelated to its cyclooxygenase (COX) inhibition. To further study the protective effect of sulindac on cells exposed to oxidative stress, we have investigated the effect of sulindac on rat cardiac myocytes subjected to hypoxia/reoxygenation, as well as in a Langendorff model of myocardial ischemia. Low levels of sulindac could protect cardiac myocytes against cell death due to hypoxia/reoxygenation. In the Langendorff model sulindac provided significant protection against cell death, when the drug was fed to the animals before the removal of the heart for the Langendorff procedure. The results indicate that the primary protective effect of sulindac in these experiments does not involve its role as a COX inhibitor. Numerous signaling pathways have been implicated in myocardial protective mechanisms, many of which involve fluctuations in reactive oxygen species (ROS) levels. The results suggest that low levels of sulindac can induce a preconditioning response, triggered by ROS, to protect cardiac tissues against oxidative damage. Blocking of preconditioning pathways by administration of the PKC blocker chelerythrine abrogated the ischemic protection afforded by sulindac. Secondly, after feeding of sulindac, two end-effectors of preconditioning, inducible nitric oxide synthase and heat shock protein 27, were found to be markedly induced in the heart, dependent on PKC. These results suggest that sulindac may have therapeutic potential as a preconditioning agent.cardioprotection ͉ myocardial ischemia

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Section: Discussionmentioning

confidence: 99%

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Moench

Prentice

Rickaway³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Both cell lines are aggressive and represent subclasses of breast cancer that do not respond well to endocrine therapy but are growth-inhibited by TCDD and MCDF (Zhang et al, 2009). The pharmaceuticals (and their applications) include leflunomide (anti-inflammatory), flutamide (antiandrogen), nimodipine (calcium channel blocker), mexiletine (antiarrhythmic), and sulindac (anti-inflammatory), which induce CYP1A1 rodent systems (in vivo and in vitro) (Ciolino et al, 2006;Hu et al, 2007;O'Donnell et al, 2010); tranilast (antiallergic drug), which exhibits AHR agonist activity and inhibits breast cancer cell and stem cell growth (Prud'homme et al, 2010); 4-hydroxytamoxifen, which induces CYP1A1/ 1B1 in breast cancer cells and suppresses osteoclast differentiation (DuSell et al, 2010); and omeprazole (Quattrochi and Tukey, 1993;Dzeletovic et al, 1997;Hu et al, 2007), which also induces CYP1A1 and exhibits other AHR agonist activities. We investigated the effects of these pharmaceuticals on AHR expression, CYP1A1 (protein and mRNA), CYP1B1 mRNA and protein, and functional responses in MDA-MB-468 and BT474 cells and compared these effects with results for TCDD.…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Jin

Lee

Safe

2012

J Pharmacol Exp Ther

105

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Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHRactive pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context.

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“…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.…”

Section: Sulindac Metabolites Detected In Normal Ratmentioning

confidence: 99%

“…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.…”

Section: With Either (R)-or (S)-sulindac After the Pretreatment Perimentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Brunell¹,

Sagher²,

Kesaraju³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that has also been studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a methyl sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R-and S-epimers. Because epimers of a compound can have very different chemical and biological properties, we have separated the R-and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

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Sulindac regulates the aryl hydrocarbon receptor-mediated expression of Phase 1 metabolic enzymes in vivo and in vitro

Cited by 32 publications

References 32 publications

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

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

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