Format

Send to

Choose Destination
Neoplasia. 2012 Feb;14(2):159-68.

Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice.

Author information

1
Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Abstract

Retinoid X receptor (RXR) has been implicated in several neoplastic diseases. Previously, we have shown that RXR-α is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics). Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in Apc(Min/+) mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-Apc(Min/+) mice (nine mice per group) were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015) and 60% (P < .0001) in males, respectively, and by 8.5% and 37% (P < .007) in females, respectively. Also, significant inhibition (50%-100%) of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001); however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001), cyclin D1, and cyclooxygenase 2 and increased RXR-α messenger RNA and uptake of oleate (34%, P < .01). Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%-72%, P < .0001) and inflammatory cytokines.

PMID:
22431924
PMCID:
PMC3306261
DOI:
10.1593/neo.111440
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center