title: Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt-signaling.
abstract: BACKGROUND
  Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of colorectal cancer. Surgery and chemoprevention are the most effective means to prevent cancer development. Thymoquinone (TQ) is considered the main compound of the volatile Nigella sativa seed oil and has been reported to possess anticarcinogenic properties. In this study we evaluated the chemopreventive properties of TQ in a mouse model of FAP.
  
  
  METHODS
  APCMin mice were fed with chow containing 37.5 mg/kg or 375 mg/kg TQ for 12 weeks. H&E stained intestine tissue sections were assessed for tumor number, localization, size, and grade. Immunohistochemistry for β-catenin, c-myc, Ki-67 and TUNEL-staining was performed to investigate TQ's effect on major colorectal cancer pathways. TQ's impact on GSK-3β and β-catenin were studied in RKO cells.
  
  
  RESULTS
  375 mg/kg but not 37.5 mg/kg TQ decreased the number of large polyps in the small intestine of APCMin mice. TQ induced apoptosis in the neoplastic tissue but not in the normal mucosa. Furthermore, upon TQ treatment, β-catenin was retained at the membrane and c-myc decreased in the nucleus, which was associated with a reduced cell proliferation in the villi. In vitro, TQ activated GSK-3β, which induced membranous localization of β-catenin and reduced nuclear c-myc expression.
  
  
  CONCLUSIONS
  In summary, TQ interferes with polyp progression in ApcMin mice through induction of tumor-cell specific apoptosis and by modulating Wnt signaling through activation of GSK-3β. Nigella sativa oil (or TQ) might be useful as nutritional supplement to complement surgery and chemoprevention in FAP.
authors.affiliation: Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lang
authors.forename: Melanie
authors.initials: M
authors.lastname: Borgmann
authors.forename: Georg
authors.initials: G
authors.lastname: Oberhuber
authors.forename: Rayko
authors.initials: R
authors.lastname: Evstatiev
authors.forename: Kristine
authors.initials: K
authors.lastname: Jimenez
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Dammann
authors.forename: Manuela
authors.initials: M
authors.lastname: Jambrich
authors.forename: Vineeta
authors.initials: V
authors.lastname: Khare
authors.forename: Christoph
authors.initials: C
authors.lastname: Campregher
authors.forename: Robin
authors.initials: R
authors.lastname: Ristl
authors.forename: Christoph
authors.initials: C
authors.lastname: Gasche
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010938:Plant Oils / Q000737:chemistry; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D029974:Carum
chemical_list: D016588:Anticarcinogenic Agents; D016227:Benzoquinones; D010938:Plant Oils; D051176:beta Catenin; C104525:caraway oil; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C003466:thymoquinone