title: Coumestrol from the national cancer Institute's natural product library is a novel inhibitor of protein kinase CK2.
abstract: BACKGROUND
  Casein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute.
  
  
  METHODS
  The quantitative luminescent kinase assay ADP-Glo™ was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo(®) was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.
  
  
  RESULTS
  We identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC(50) value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines.
  
  
  CONCLUSIONS
  Our study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC(50), had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Hsieh
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Yang
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Csaba
authors.initials: C
authors.lastname: Peto
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.forename: Liang
authors.initials: L
authors.lastname: You
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003375:Coumestrol / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D054547:National Cancer Institute (U.S.); D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014481:United States
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D047390:Casein Kinase II; D003375:Coumestrol