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Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin
R G Tunstall1, R A Sharma, S Perkins
1Cancer Biomarkers and Prevention Group, Departments of Cancer Studies and Biochemistry, University of Leicester, Leicester LE2 7LX, UK.
Abstract:
The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We have studied COX-2 protein expression and oxidative DNA adduct levels in intestinal adenoma tissue from Apc(Min+) mice to try and differentiate between curcumin's direct pharmacodynamic effects and indirect effects via its inhibition of adenoma growth. Mice received dietary curcumin (0.2%) for 4 or 14 weeks. COX-2 protein, M1dG and 8-oxo-dG levels were measured by Western blot, immunochemical assay and liquid chromatography-mass spectrometry, respectively. In control Apc(Min+) mice, the levels of all three indices measured in adenoma tissue were significantly higher than levels in normal mucosa. Lifetime administration of curcumin reduced COX-2 expression by 66% (P = 0.01), 8-oxo-dG levels by 24% (P < 0.05) and M1dG levels by 39% (P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M1dG levels by 43% (P < 0.01). COX-2 protein levels related to adenoma size. These results demonstrate the utility of measuring these oxidative DNA adduct levels to show direct antioxidant effects of dietary curcumin. The effects of long-term dietary curcumin on COX-2 protein levels appear to reflect retardation of adenoma development.
Insights
Curcumin, a natural polyphenol, inhibits intestinal adenoma growth in mice by reducing cyclooxygenase-2 (COX-2) and oxidative DNA damage. These findings highlight curcumin
Area of Science:
- * Molecular Biology
- * Cancer Research
- * Nutritional Science
Background:
- * Familial adenomatous polyposis is a precursor to colorectal cancer.
- * Curcumin, a natural polyphenol, shows promise in preclinical models for cancer prevention.
- * Cyclooxygenase-2 (COX-2) and oxidative DNA adducts (M1dG, 8-oxo-dG) are implicated in adenoma development.
Purpose of the Study:
- * To investigate the effects of dietary curcumin on COX-2 protein and oxidative DNA adducts in intestinal adenomas.
- * To differentiate between direct pharmacodynamic effects and indirect effects of curcumin on adenoma growth.
- * To assess the utility of oxidative DNA adducts as biomarkers for curcumin's antioxidant activity.
Main Methods:
- * Apc(Min+) mice, a model for human familial adenomatous polyposis, were fed a diet containing 0.2% curcumin for 4 or 14 weeks.
- * COX-2 protein expression was measured by Western blot.
- * Oxidative DNA adducts (M1dG and 8-oxo-dG) were quantified using immunochemical assays and liquid chromatography-mass spectrometry.
Main Results:
- * Adenoma tissue showed significantly higher levels of COX-2, M1dG, and 8-oxo-dG compared to normal mucosa.
- * Long-term curcumin administration reduced COX-2 expression by 66%, 8-oxo-dG by 24%, and M1dG by 39%.
- * Short-term curcumin feeding decreased M1dG by 43% and showed a correlation between COX-2 levels and adenoma size.
Conclusions:
- * Dietary curcumin exhibits direct antioxidant effects, evidenced by reduced oxidative DNA adducts.
- * Long-term curcumin intake appears to retard adenoma development, partly through COX-2 inhibition.
- * Oxidative DNA adduct levels serve as valuable indicators of curcumin's direct biological effects.
