Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ mice

Neoplasia. 2010 Jan;12(1):95-102. doi: 10.1593/neo.91718.


Chemopreventive effects and associated mechanisms of grape seed extract (GSE) against intestinal/colon cancer development are largely unknown. Herein, we investigated GSE efficacy against intestinal tumorigenesis in APC(min/+) mice. Female APC(min/+) mice were fed control or 0.5% GSE (wt/wt) mixed AIN-76A diet for 6 weeks. At the end of the experiment, GSE feeding decreased the total number of intestinal polyps by 40%. The decrease in polyp formation in the small intestine was 42%, which was mostly in its middle (51%) and distal (49%) portions compared with the proximal one. GSE also decreased polyp growth where the number of polyps of 1 to 2 mm in size decreased by 42% and greater than 2 mm in size by 71%, without any significant change in polyps less than 1 mm in size. Immunohistochemical analyses of small intestinal tissue samples revealed a decrease (80%-86%) in cell proliferation and an increase (four- to eight-fold) in apoptosis. GSE feeding also showed decreased protein levels of cyclooxygenase-2 (COX-2) (56%-64%), inducible nitric oxide synthase (iNOS) (58%-60%), and beta-catenin (43%-59%) but an increased Cip1/p21-positive cells (1.9- to 2.6-fold). GSE also decreased cyclin D1 and c-Myc protein levels in small intestine. Together, these findings show the chemopreventive potential of GSE against intestinal polyp formation and growth in APC(min/+) mice, which was accompanied with reduced cell proliferation and increased apoptosis together with down-regulation in COX-2, iNOS, beta-catenin, cyclin D1, and c-Myc expression, but increased Cip1/p21. In conclusion, the present study suggests potential usefulness of GSE for the chemoprevention of human intestinal/colorectal cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenomatous Polyposis Coli Protein / deficiency
  • Adenomatous Polyposis Coli Protein / genetics*
  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Intestinal Polyps / genetics
  • Intestinal Polyps / metabolism
  • Intestinal Polyps / prevention & control*
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Mice
  • Mice, Mutant Strains
  • Mutation, Missense
  • Nitric Oxide Synthase Type II / metabolism
  • Plant Extracts / administration & dosage
  • Plant Extracts / pharmacology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Vitis / chemistry*
  • beta Catenin / metabolism


  • Adenomatous Polyposis Coli Protein
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Myc protein, mouse
  • Plant Extracts
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-myc
  • beta Catenin
  • Cyclin D1
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2