Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials.
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.
Tunstall
R G
RG
Cancer Biomarkers and Prevention Group, Departments of Cancer Studies and Biochemistry, University of Leicester, Leicester LE2 7LX, UK.
Sharma
R A
RA
Perkins
S
S
Sale
S
S
Singh
R
R
Farmer
P B
PB
Steward
W P
WP
Gescher
A J
AJ
D011125:Adenomatous Polyposis Coli / Q000178:diet therapy*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003474:Curcumin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL
D018736:DNA Adducts; D051546:Cyclooxygenase 2; D003474:Curcumin