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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.
AuthorsFlor D Mora, Deborah K Jones, Prashant V Desai, Akshay Patny, Mitchell A Avery, Dennis R Feller, Troy Smillie, Yu-Dong Zhou, Dale G Nagle
JournalJournal of natural products (J Nat Prod) Vol. 69 Issue 4 Pg. 547-52 (Apr 2006) ISSN: 0163-3864 [Print] United States
PMID16643023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Disulfides
  • Histone Deacetylase Inhibitors
  • PPAR gamma
  • psammaplin A
  • Tyrosine
Topics
  • Animals
  • Apoptosis (drug effects)
  • Breast Neoplasms
  • Disulfides (chemistry, isolation & purification, pharmacology)
  • Dose-Response Relationship, Drug
  • Female
  • Histone Deacetylase Inhibitors
  • Humans
  • Micronesia
  • PPAR gamma (agonists)
  • Porifera (chemistry)
  • Tyrosine (analogs & derivatives, chemistry, isolation & purification, pharmacology)

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