A novel peroxisome proliferator-activated receptor delta antagonist, SR13904, has anti-proliferative activity in human cancer cells

The peroxisome proliferator-activated receptor delta (PPAR delta) 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 PPAR delta agonist-induced transactivation and functions as a PPAR delta antagonist. SR13904 also antagonizes PPAR gamma 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 PPAR delta. The antitumor activities of SR13904 suggest that antagonism of PPAR delta-mediated transactivation may inhibit tumorigenesis and that pharmacological inhibition of PPAR delta may be a potential strategy for treatment or prevention of cancer.