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Departments of ¹ Veterinary Physiology and Pharmacology, ² Veterinary Anatomy and Public Health, and ³ Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX; and ⁴ Institute of Biosciences and Technology, Texas A&M University System, Health Science Center, Houston, TX

Requests for Reprints: Stephen Safe, Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, 4466 TAMU, Veterinary Research Building 409, College Station, TX 77843-4466. Phone: (979) 845-5988; Fax: (979) 862-4929. E-mail: ssafe{at}cvm.tamu.edu

1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF₃) and several p-substituted phenyl analogues have been investigated as a new class of peroxisome proliferator-activated receptor (PPAR) agonists. Structure-activity studies in PPAR-dependent transactivation assays in MCF-7 breast cancer cells show that 5–20 µM concentrations of compounds containing p-trifluoromethyl, t-butyl, cyano, dimethylamino, and phenyl groups were active, whereas p-methyl, hydrogen, methoxy, hydroxyl, or halogen groups were inactive as PPAR agonists. Induction of PPAR-dependent transactivation by 15-deoxy-12,14-prostaglandin J2 (PGJ2) and DIM-C-pPhCF₃ was inhibited in MCF-7 cells cotreated with the PPAR-specific antagonist N-(4'-aminopyridyl)-2-chloro-5-nitrobenzamide. In mammalian two-hybrid assays, DIM-C-pPhCF₃ and PGJ2 (5–20 µM) induced interactions of PPAR with steroid receptor coactivator (SRC) 1, SRC2 (TIFII), and thyroid hormone receptor-associated protein 220 but not with SRC3 (AIB1). In contrast, DIM-C-pPhCF₃, but not PGJ2, induced interactions of PPAR with PPAR coactivator-1. C-substituted diindolylmethanes inhibit carcinogen-induced rat mammary tumor growth, induce differentiation in 3T3-L1 preadipocytes, inhibit MCF-7 cell growth and G₀/G₁-S phase progression, induce apoptosis, and down-regulate cyclin D1 protein and estrogen receptor in breast cancer cells. These compounds are a novel class of synthetic PPAR agonists that induce responses in MCF-7 cells similar to those observed for PGJ2.

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Received 7/29/03; revised 1/ 5/04; accepted 1/ 9/04.

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