title: Resveratrol in combination with other dietary polyphenols concomitantly enhances antiproliferation and UGT1A1 induction in Caco-2 cells.
abstract: OBJECTIVE
  The only FDA approved medication for colorectal cancer (CRC) prevention is celecoxib. Its adverse effects underline the need for safer drugs. Polyphenols like resveratrol are in clinical trials for this purpose. This study aimed at examining effects of resveratrol alone and in combination with curcumin or chrysin on UGT induction in Caco-2 cells. Phytochemical combinations were selected using drug combination analyses of various anti-proliferation ratios of resveratrol+curcumin and resveratrol+chrysin.
  
  
  METHODS
  Cell proliferation and UGT1A1 induction assays were carried out with individual polyphenols and combinations. Cell viability was determined with AlamarBlue assays. UGT1A1 mRNA was quantified via real time RT-PCR. UGT activity was determined with 4-methylumbelliferone (4MU) glucuronidation.
  
  
  RESULTS
  Cell proliferation IC(50) estimates (± SE) for resveratrol, curcumin and chrysin were 20.8 ± 1.2, 20.1 ± 1.1 and 16.3 ± 1.3μM respectively. Combination of anti-proliferative effects showed additivity for resveratrol+chrysin and resveratrol+curcumin. Resveratrol at its IC(50) mediated a four-fold induction of UGT1A1 mRNA in a concentration independent manner. Chrysin at its IC(50) induced UGT1A1 expression seven-fold while Curcumin at its IC(90) mediated a two-fold induction. The 20 μM:40μ M resveratrol+curcumin and 20 μM :32 μM resveratrol+chrysin combinations mediated the greatest increases in mRNA expression (12 and 22 folds respectively). Significant increase in 4-MU glucuronidation was observed with combinations exhibiting maximal mRNA induction.
  
  
  CONCLUSIONS
  Phytochemical combinations can offer greater chemoprevention than single agents. These chemicals might offer safer options than present synthetic therapeutics for CRC prevention.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, United States.
authors.forename: Otito F
authors.initials: OF
authors.lastname: Iwuchukwu
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Tallarida
authors.forename: Swati
authors.initials: S
authors.lastname: Nagar
mesh_terms: D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000517:prevention & control; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
chemical_list: D016588:Anticarcinogenic Agents; D003474:Curcumin; D005419:Flavonoids; D020719:Glucuronides; D014453:Glucuronosyltransferase; D012333:RNA, Messenger; D000077185:Resveratrol; D013267:Stilbenes; D000099148:UGT1A1 Enzyme; C043561:chrysin