Death receptor 5 targeting activity-guided isolation of isoflavones from Millettia brandisiana and Ardisia colorata and evaluation of ability to induce TRAIL-mediated apoptosis

Bioorg Med Chem. 2009 Feb 1;17(3):1181-6. doi: 10.1016/j.bmc.2008.12.033. Epub 2008 Dec 24.


Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor for TNF-related apoptosis-inducing ligand (TRAIL). On screening for compounds that enhance DR5 expression using a luciferase assay with DLD-1/SacI, we previously identified 4'-demethyltoxicarol isoflavone (1) isolated from the leaves of Millettia brandisiana. In this study, we revealed that 1 sensitized TRAIL-resistant human gastric adenocarcinoma (AGS) cells to TRAIL-induced apoptosis by up-regulating the expression of DR5. 1 induced DR5 expression at both the mRNA and protein level. A human recombinant DR5/Fc chimera remarkably inhibited 1-induced apoptosis. These results suggest that the enhancement of DR5 expression by 1 was critical to the cell death. Furthermore, a MeOH extract of the bark of Ardisia colorata markedly enhanced DR5 activity in this screening system. Bioassay-guided fractionation of A. colorata led to the isolation and identification of a new isoflavone, coloratanin A (3), together with ten known compounds. The chemical structure of the new compound was elucidated on the basis of a spectroscopic analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Ardisia / chemistry*
  • Cell Line, Tumor
  • Humans
  • Isoflavones / chemistry
  • Isoflavones / isolation & purification
  • Isoflavones / pharmacology*
  • Millettia / chemistry*
  • Plant Bark / chemistry
  • Plant Leaves / chemistry
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Up-Regulation


  • Isoflavones
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Fusion Proteins
  • TNF-Related Apoptosis-Inducing Ligand