| First Author | Hasson RM | Year | 2014 |
| Journal | Biochem Biophys Res Commun | Volume | 444 |
| Issue | 3 | Pages | 283-9 |
| PubMed ID | 24486542 | Mgi Jnum | J:219148 |
| Mgi Id | MGI:5619707 | Doi | 10.1016/j.bbrc.2013.11.135 |
| Citation | Hasson RM, et al. (2014) Lack of anti-tumor activity with the beta-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis. Biochem Biophys Res Commun 444(3):283-9 |
| abstractText | BACKGROUND: Previously, we showed that short-term inhibition of beta-catenin expression and reversal of aberrant beta-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective beta-catenin chemoprevention. In this study, we hypothesized that disruption of beta-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based beta-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. MATERIALS AND METHODS: C57BL/6J Apc(+/+) wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30mg/kg). Drug effect on tumor numbers, beta-catenin protein expression, and nuclear beta-catenin localization were determined. RESULTS: Although the tumor phenotype and beta-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in beta-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to beta-catenin ablation in the intestinal tissue and loss of function. CONCLUSIONS: Our data support the critical role of Wnt/beta-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function. |
