title: Raloxifene and antiestrogenic gonadorelin inhibits intestinal tumorigenesis by modulating immune cells and decreasing stem-like cells.
abstract: Studies suggest that estrogen plays a contributing role in colorectal cancer. This project examined the preventive effects of raloxifene, a selective estrogen receptor modulator (SERM), and gonadorelin, an antiestrogenic drug, in female Apc(Min/+) mouse intestinal tumorigenesis. Six-week-old Apc(Min/+)mice were fed diet containing 1 ppm raloxifene or control diet. Gonadorelin (150 ng/mouse) was injected subcutaneously into one treatment group. Intestinal tumors were evaluated for tumor multiplicity and size. Mice treated with raloxifene and gonadorelin showed colon tumor inhibition of 80% and 75%, respectively. Both drugs significantly inhibited small intestinal tumor multiplicity and size (75%-65%, P < 0.0001). Raloxifene and gonadorelin showed significant tumor inhibition with 98% and 94% inhibition of polyps >2 mm in size. In mice fed with raloxifene or injected with gonadorelin, tumors showed significantly reduced proliferating cell nuclear antigen expression (58%-65%, P < 0.0001). Raloxifene treatment decreased β-catenin, cyclin D1, laminin 1β, Ccl6, and stem-like cells (Lgr 5, EpCAM, CD44/CD24), as well as suppressed inflammatory genes (COX-2, mPGES-1, 5-LOX,). Gonadorelin showed significant decrease in COX-2, mPGES-1, iNOS, and stem-like cells or increased NK cells and chemokines required for NK cells. Both drugs were effective in suppressing tumor growth albeit with different mechanisms. These observations show that either suppression of estrogen levels or modulation of estrogen receptor dramatically suppresses small intestinal and colonic tumor formation in female Apc(Min/+) mice. These results support the concept of chemoprevention by these agents in reducing endogenous levels of estrogen or modulating ER signaling.
authors.affiliation: Center for Cancer Prevention and Drug Development (CCPDD), Department of Medicine, Hematology Oncology Section, 975 NE 10th Street, BRC 1209, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. njanakir@ouhsc.edu.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Misty
authors.initials: M
authors.lastname: Brewer
authors.forename: Taylor
authors.initials: T
authors.lastname: Bryant
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.forename: Gopal
authors.initials: G
authors.lastname: Pathuri
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Gali
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects* / Q000473:pathology; D002452:Cell Count; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D007111:Immunity, Cellular / Q000187:drug effects; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D004965:Estrogen Antagonists; D020845:Selective Estrogen Receptor Modulators; D007987:Gonadotropin-Releasing Hormone; D020849:Raloxifene Hydrochloride