title: A novel peroxisome proliferator-activated receptor delta antagonist, SR13904, has anti-proliferative activity in human cancer cells.
abstract: The peroxisome proliferator-activated receptor delta (PPARdelta) is a ligand-activated, nuclear receptor transcription factor that has a documented role in glucose and lipid homeostasis. Recent studies have implicated this nuclear receptor in numerous aspects of oncogenesis. We report herein the characterization of a novel small-molecule (SR13904) that inhibits PPARdelta agonist-induced transactivation and functions as a PPARdelta antagonist. SR13904 also antagonizes PPARgamma transactivation, albeit with much weaker potency. SR13904 displays inhibitory effects on cellular proliferation and survival in several human carcinoma lines, including lung, breast and liver. These inhibitory effects of SR13904 on tumor cells were linked to a G(1)/S cell cycle block and increased apoptosis. Molecular studies show that SR13904 treatment of a lung cancer cell line, A549, results in markedly reduced levels of a number of cell cycle proteins including cyclin A and D, and cyclin dependent kinase (CDK) 2 and 4. The inhibitory effects on CDK2 appear to be transcriptional. Several of these cell cycle-related genes are known to be upregulated by PPARdelta. The antitumor activities of SR13904 suggest that antagonism of PPARdelta-mediated transactivation may inhibit tumorigenesis and that pharmacological inhibition of PPARdelta may be a potential strategy for treatment or prevention of cancer.
authors.affiliation: SRI International, Menlo Park, CA, USA. nzaveri@mmrx.org
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Sato
authors.forename: Faming
authors.initials: F
authors.lastname: Jiang
authors.forename: Joy
authors.initials: J
authors.lastname: Calaoagan
authors.forename: Keith R
authors.initials: KR
authors.lastname: Laderoute
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D047494:PPAR delta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D056741:Cyclin D; D006131:Growth Inhibitors; D047494:PPAR delta; C549080:SR13904; D013844:Thiazoles; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4