Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Dae J. Kim, Kumble Sandeep Prabhu, Frank J. Gonzalez, Jeffrey Maurice Peters

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19 Citations (Scopus)

Abstract

Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-β (PPARβ), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARβ either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARβ in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARβ-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARβ-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE2 and PGI2. Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARβ. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARβ by COX-derived metabolites potentiates chemically induced skin carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1105-1112
Number of pages8
JournalCarcinogenesis
Volume27
Issue number5
DOIs
StatePublished - May 1 2006

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Sulindac
Peroxisome Proliferator-Activated Receptors
Carcinogenesis
Skin
Cyclooxygenase 2
Ligands
Prostaglandins
Anti-Inflammatory Agents
Diet
Chemoprevention
Non-Steroidal Anti-Inflammatory Agents
Epoprostenol
Dinoprostone
Biological Assay
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

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title = "Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)",
abstract = "Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-β (PPARβ), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARβ either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARβ in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARβ-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARβ-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE2 and PGI2. Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARβ. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARβ by COX-derived metabolites potentiates chemically induced skin carcinogenesis.",
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AU - Gonzalez, Frank J.

AU - Peters, Jeffrey Maurice

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AB - Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-β (PPARβ), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARβ either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARβ in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARβ-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARβ-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE2 and PGI2. Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARβ. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARβ by COX-derived metabolites potentiates chemically induced skin carcinogenesis.

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