Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC is initiated by mutations of the tumor suppressor gene, adenomatous polyposis coli (APC) or β-catenin gene. These mutations stabilize β-catenin and constitutively activate Wnt/β-catenin target genes, such as c-Myc and Cyclin D1, ultimately leading to cancer. Naturally occurring stilbene derivatives, resveratrol and pterostilbene, inhibit Wnt signaling and repress CRC cell proliferation but are ineffective at concentrations lower than 10 µM. To understand the structure/activity relationship within these stilbene derivatives and to develop more efficacious Wnt inhibitors than these natural products, we synthesized and evaluated a panel of fluorinated N,N-dialkylaminostilbenes. Among this panel, (E)-4-(2,6-difluorostyryl)-N,N-dimethylaniline (4r) inhibits Wnt signaling at nanomolar levels and inhibits the growth of human CRC cell xenografts in athymic nude mice at a dosage of 20mg/kg. These fluorinated N,N-dialkylaminostilbenes appear to inhibit Wnt signaling downstream of β-catenin, probably at the transcriptional level.

Background: Bmi1 is a potential marker for the intestinal stem cells. Results: Wnt regulates Bmi1 indirectly, while KLF4 directly inhibits Bmi1, as well as Bmi1-mediated histone ubiquitination in colon cancer cells. Conclusion: Bmi1 is required for colon cancer cell proliferation, and it is up-regulated in colon cancer tissues. Significance: Study of the mechanisms of Bmi1 regulation suggests potential targets for cancer therapeutics.