Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: Modification by dietary curcumin and implications for clinical trials

• Published in: European journal of cancer (1990) 2006-02, Vol.42 (3), p.415-421
• Main Authors: Tunstall, R.G., Sharma, R.A., Perkins, S., Sale, S., Singh, R., Farmer, P.B., Steward, W.P., Gescher, A.J.
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli - diet therapy; Analysis of Variance; Animals; Biological and medical sciences; Blotting, Western; Chemoprevention; Colorectal carcinogenesis; Curcumin - pharmacology; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; DNA Adducts - drug effects; DNA damage; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2005.10.024

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 (M 1dG) 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, M 1dG 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 M 1dG levels by 39% ( P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M 1dG 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.