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


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.
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Rian M
RM
Hasson
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Alexandra
A
Briggs
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Hira
H
Rizvi
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Adelaide M
AM
Carothers
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Jennifer S
JS
Davids
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States.
Monica M
MM
Bertagnolli
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, United States. Electronic address: nlcho@partners.org.
Nancy L
NL
Cho
D000818:Animals; D063646:Carcinogenesis; D004195:Disease Models, Animal; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007422:Intestines / Q000187:drug effects; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
C588188:EZN-3892; D009841:Oligonucleotides; D051176:beta Catenin
Colorectal adenoma; Colorectal cancer; Interfering RNA; Min/+ mouse; β-Catenin