title: Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice.
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.
authors.affiliation: 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.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Chang-In
authors.initials: CI
authors.lastname: Choi
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism / Q000517:prevention & control*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000077610:Bexarotene; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D019301:Oleic Acid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D014280:Triglycerides / Q000097:blood
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D016588:Anticarcinogenic Agents; C530105:Ccnd1 protein, mouse; D016207:Cytokines; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D019938:Cyclin D1; D019301:Oleic Acid; D000077610:Bexarotene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2