title: Bioassay for the identification of natural product-based activators of peroxisome proliferator-activated receptor-gamma (PPARgamma): the marine sponge metabolite psammaplin A activates PPARgamma and induces apoptosis in human breast tumor cells.
abstract: Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor (NHR) family, are ligand-activated transcription factors. Ligands (agonists) of PPARgamma have been shown to inhibit growth, promote terminal differentiation, and induce apoptosis in human breast tumor cells. A cell-based reporter assay was developed to examine extracts of terrestrial and marine organisms for the ability to activate PPARgamma. Bioassay-guided fractionation and isolation of an active extract from Pseudoceratina rhax yielded the known histone deacetylase (HDAC) inhibitor psammaplin A (1). Compound 1 activates PPARgamma in a MCF-7 cell-based reporter assay and induces apoptosis in human breast tumor cells in vitro. Molecular modeling studies suggest that 1 may interact with binding sites within the PPARgamma ligand-binding pocket. Therefore, in addition to its known effects on HDAC-mediated processes, activation of PPARgamma-regulated gene expression may play a role in the ability of 1 to induce apoptosis.
authors.affiliation: Department of Pharmacognosy, and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Flor D
authors.initials: FD
authors.lastname: Mora
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Jones
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Desai
authors.forename: Akshay
authors.initials: A
authors.lastname: Patny
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Feller
authors.forename: Troy
authors.initials: T
authors.lastname: Smillie
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D004220:Disulfides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008849:Micronesia; D047495:PPAR gamma / Q000819:agonists*; D011161:Porifera / Q000737:chemistry*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D004220:Disulfides; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; C098378:psammaplin A; D014443:Tyrosine