LB-349

Background: We show elsewhere that low concentrations of resveratrol (Res) which have minimal effect on cell proliferation or apoptosis induction can inhibit Wnt signaling in vitro. Wnt signaling is activated in over 85% of sporadic colon cancers.

Objective: To determine whether low dosages of Res or Res-containing freeze dried grape powder (GP) inhibit Wnt signaling in normal colonic mucosa and colon cancer.
 >Methodology: 6 patients with colorectal cancer have been enrolled to-date onto a phase I dose de-escalation trial. Two patients each received resveratrol 20mg (a non-pure nutritional supplement tablet derived from grape extract purchased commercially), GP 120mg (0.114mg Res) or GP 80mg (0.073mg Res) for two weeks prior to surgical resection of colorectal cancer. GP is made of freeze dried whole grapes (detailed compositional analysis available from Cal. Table Grape Commission). Biopsies of normal mucosa and colorectal cancer were obtained prior to Res/GP by colonoscopy and following Res/GP at the time of surgery. Tissue samples were processed for RNA and analyzed with a Wnt specific microarray.
 >Results: Neither Res or GP had any effect on the expression of frizzled receptors, Wnt ligands or Wnt inhibitory molecules. A panel of 7 Wnt target genes, including c-myc and cyclinD1 were evaluated to define any effect on Wnt signal throughput. Overall, in normal mucosa, Res/GP reduced the expression of each of the target genes except for LEF1 (slight increase), nemo-like kinase (no change) and FGF4 (no change). c-myc was reduced by 54%, jun by 26% and cyclinD1 by 28%. The most marked effect occurred with the lowest dose (Res equivalents) tested, GP80. The composite expression of target genes was significantly reduced by 47% following GP80 compared to the pre-GP80 baseline (p<0.001). Changes in the composite target gene expression in normal colonic mucosa for Res20 and GP120 were not statistically significant. In the colorectal cancer tissue, Res/GP had a paradoxical effect, slightly increasing expression of c-myc, jun and cyclinD1 while slightly decreasing expression of LEF1, nemo and FGF4.
 >Conclusions: Low dose Res/GP affects the expression of a panel of Wnt target genes in vivo in normal colonic mucosa and colorectal cancer, with distinct effects on each of these tissues. Measurement of Wnt target gene expression is a sensitive measure of the effect of low dose Res/GP in colonic mucosa. The reduction in Wnt target gene expression in normal mucosa following Res/GP suggests that low dose Res-containing formulations or foodstuffs could be potentially beneficial for colorectal cancer prevention.
 >Support: California Table Grape Commission and UCLA Clinical Nutrition Research Unit.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA