title: Death receptor 5 targeting activity-guided isolation of isoflavones from Millettia brandisiana and Ardisia colorata and evaluation of ability to induce TRAIL-mediated apoptosis.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohtsuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyano
authors.forename: Thaworn
authors.initials: T
authors.lastname: Kowithayakorn
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D017209:Apoptosis; D031644:Ardisia / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D033641:Millettia / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D007529:Isoflavones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand