Discovery of New Drugs That Target Peroxisomal Proliferator-Activated Receptor Gamma (PPAR-Gamma) for the Treatment of Breast Tumors
Abstract
The major goal of this project is to discover novel chemotherapeutic agents that act on a newly discovered molecular target in breast tumor cells. Recent studies have demonstrated that substances that activate the nuclear hormone receptor/transcription factor, Peroxisome Proliferator-Activated Receptors-gamma (PPAR-gamma) can inhibit growth, cause terminal differentiation, and induce apoptosis in human breast tumor cells. In vitro molecular mechanism-targeted pharmacological assays were developed and used to discover small (drug-like) PPAR-gamma activators from chemically-rich marine organisms. Chemically unique marine oxylipins (structurally novel lipoxygenase metabolites of marine fatty acids) were shown to act as PPAR-gamma ligands, transactivate PPAR-gamma gene expression, induce cellular arrest, and cause cell death in MCF-7 breast tumor cells in vitro. Most currently know PPAR-gamma activators are fatty acid metabolites or structurally related to the synthetic thiazoilidinedione (TZD) class of insulin sensitizers. This research has discovered that cyanobacteria and marine algae produce natural products, found nowhere else in nature, that activate PPAR-gamma. These structurally unique marine natural products are chemically unrelated to any other class of known PPAR-gamma activators. It is envisioned that these novel chemical prototypes can be used as 'chemical ideas' to design new antitumor agents that function through the activation of PPAR-gamma.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADB274459
Entities
People
- Dale Nagle
Organizations
- Mississippi State University