Lack of anti-tumor activity with the β-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis

Biochem Biophys Res Commun. 2014 Feb 14;444(3):283-9. doi: 10.1016/j.bbrc.2013.11.135. Epub 2014 Jan 31.

Abstract

Background: Previously, we showed that short-term inhibition of β-catenin expression and reversal of aberrant β-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 β-catenin chemoprevention. In this study, we hypothesized that disruption of β-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based β-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, β-catenin protein expression, and nuclear β-catenin localization were determined.

Results: Although the tumor phenotype and β-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in β-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 β-catenin ablation in the intestinal tissue and loss of function.

Conclusions: Our data support the critical role of Wnt/β-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function.

Keywords: Colorectal adenoma; Colorectal cancer; Interfering RNA; Min/+ mouse; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • Disease Models, Animal
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology*
  • Intestines / drug effects
  • Maximum Tolerated Dose
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotides / pharmacology*
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism

Substances

  • EZN-3892
  • Oligonucleotides
  • beta Catenin