title: Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc(-/+) mice.
abstract: BACKGROUND
  Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Colorectal cancers have a prolonged latency following initiation that may span decades providing ample time for implementing a chemoprevention strategy that could block or reverse the progression to CRC. Cdk4 pathway alterations have been linked to a number of cancers including CRC. In these experiments we focused on the Cdk4 pathway and its role in intestinal tumorigenesis as a possible target in chemoprevention strategies.
  
  
  METHODS
  We evaluated the effect of Cdk4 blockade on the prevention of intestinal tumor formation by crossing Cdk4(-/-) mice to Apc(-/+) mice. In addition, we tested the effect of the dietary compound silibinin on the Cdk4 pathway in Apc(-/+) mice and HT-29 colon cancer cells in culture.
  
  
  RESULTS
  Cdk4(-/-) mice backcrossed to Apc(-/+) mice reduced intestinal adenoma formation compared to Apc(-/+) controls. Silibinin effectively targeted the Cdk4 pathway causing hypophosphorylation of the retinoblastoma protein, inhibited cell growth, and induced apoptosis. As a result silibinin blocked the development of intestinal adenomas by 52% in this genetic model (Apc(-/+) mice) of early events in colorectal cancer formation. No toxic abnormalities were detected in mice which received silibinin.
  
  
  CONCLUSIONS
  Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas.
authors.affiliation: Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD 21205, USA. bkarim@jhmi.edu
authors.forename: Baktiar O
authors.initials: BO
authors.lastname: Karim
authors.forename: Ki-Jong
authors.initials: KJ
authors.lastname: Rhee
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liu
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Zheng
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; D012838:Silymarin; D019938:Cyclin D1; D000077385:Silybin; D051358:Cyclin-Dependent Kinase 4