title: Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice.
abstract: BACKGROUND
  Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms.
  
  
  RESULTS
  We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of β-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac.
  
  
  CONCLUSIONS
  The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.
authors: School of Life Sciences, Liaoning University, Shenyang 110036, China.
authors: Xiuli
authors: X
authors: Bi
authors: Nicole
authors: N
authors: Pohl
authors: Huali
authors: H
authors: Dong
authors: Wancai
authors: W
authors: Yang
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012643:Selenium / Q000494:pharmacology*; D013467:Sulindac / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013467:Sulindac; D048055:Mitogen-Activated Protein Kinase 8; D012643:Selenium