Lack of anti-tumor activity with the ß-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis.
Biochem Biophys Res Commun
; 444(3): 283-9, 2014 Feb 14.
Article
em En
| MEDLINE
| ID: mdl-24486542
ABSTRACT
BACKGROUND:
Previously, we showed that short-term inhibition of ß-catenin expression and reversal of aberrant ß-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 ß-catenin chemoprevention. In this study, we hypothesized that disruption of ß-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based ß-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. MATERIALS ANDMETHODS:
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, ß-catenin protein expression, and nuclear ß-catenin localization were determined.RESULTS:
Although the tumor phenotype and ß-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in ß-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 ß-catenin ablation in the intestinal tissue and loss of function.CONCLUSIONS:
Our data support the critical role of Wnt/ß-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
/
Beta Catenina
/
Carcinogênese
/
Neoplasias Intestinais
Limite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos