title: A new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes.
abstract: 1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF(3)) and several p-substituted phenyl analogues have been investigated as a new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Structure-activity studies in PPARgamma-dependent transactivation assays in MCF-7 breast cancer cells show that 5-20 micro M 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 PPARgamma agonists. Induction of PPARgamma-dependent transactivation by 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2) and DIM-C-pPhCF(3) was inhibited in MCF-7 cells cotreated with the PPARgamma-specific antagonist N-(4'-aminopyridyl)-2-chloro-5-nitrobenzamide. In mammalian two-hybrid assays, DIM-C-pPhCF(3) and PGJ2 (5-20 micro M) induced interactions of PPARgamma with steroid receptor coactivator (SRC) 1, SRC2 (TIFII), and thyroid hormone receptor-associated protein 220 but not with SRC3 (AIB1). In contrast, DIM-C-pPhCF(3), but not PGJ2, induced interactions of PPARgamma with PPARgamma coactivator-1. C-substituted diindolylmethanes inhibit carcinogen-induced rat mammary tumor growth, induce differentiation in 3T3-L1 preadipocytes, inhibit MCF-7 cell growth and G(0)/G(1)-S phase progression, induce apoptosis, and down-regulate cyclin D1 protein and estrogen receptor alpha in breast cancer cells. These compounds are a novel class of synthetic PPARgamma agonists that induce responses in MCF-7 cells similar to those observed for PGJ2.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Qin
authors.forename: Derek
authors.initials: D
authors.lastname: Morrow
authors.forename: Jessica
authors.initials: J
authors.lastname: Stewart
authors.forename: Kyle
authors.initials: K
authors.lastname: Spencer
authors.forename: Weston
authors.initials: W
authors.lastname: Porter
authors.forename: Roger
authors.initials: R
authors.lastname: Smith
authors.forename: Timothy
authors.initials: T
authors.lastname: Phillips
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002273:Carcinogens; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D003001:Cloning, Molecular; D019938:Cyclin D1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D047628:Estrogen Receptor alpha; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008697:Methane / Q000494:pharmacology*; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: C492909:1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane; D002273:Carcinogens; D047628:Estrogen Receptor alpha; D007211:Indoles; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; D019938:Cyclin D1; C037112:9-deoxy-delta-9-prostaglandin D2; D008156:Luciferases; D008697:Methane; D015230:Prostaglandin D2; C016392:3,3'-diindolylmethane