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The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

ABSTRACT: The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity. Sulindac sulfide and DM-sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of sulindac and doses of DM-sulindac. Only sulindac significantly inhibited tumor formation inAPC/Min mice. To determine the pharmacokinetic properties of sulindac and DM-sulindac in vivo, wild-type C57/B6 mice were fed with sulindac and DM-sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-sulindac to DM-sulindac sulfide (active form) was less efficient than the conversion of sulindac to sulindac sulfide (active form) in the mice. Lower levels of DM-sulindac sulfide accumulated in intestinal and colon tissues in comparison with sulindac sulfide. In addition, NAG-1/GDF15 was induced in the liver of sulindac-fed mice but not in the DM-sulindac-fed mice. Collectively, our results suggest that the tumor-inhibitory effects of sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates.

SUBMITTER: Wang X

PROVIDER: S-EPMC3970176 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

Wang Xingya X Kingsley Philip J PJ Marnett Larry J LJ Eling Thomas E TE

Cancer prevention research (Philadelphia, Pa.) 20110101 1

The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its pro ...[more]

PMID: 21205743

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Project description:BackgroundFamilial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated ApcMin/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with ApcMin/+, we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-ApcMin/+mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-ApcMin/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1-3) of small intestinal and colon were recorded.ResultsThe number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63-17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the ApcMin/+ mutation.ConclusionsGenomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements - and possible epistatic effects - located in the mapped QTL.

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The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

Publications

The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

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