Qin Chunhua, Morrow Derek, Stewart Jessica, Spencer Kyle, Porter Weston, Smith Roger, Phillips Timothy, Abdelrahim Maen, Samudio Ismael, Safe Stephen
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA.
Mol Cancer Ther. 2004 Mar;3(3):247-60.
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.
1,1-双（3'-吲哚基）-1-（对三氟甲基苯基）甲烷（DIM-C-pPhCF(3)）及几种对位取代苯基类似物已作为一类新型过氧化物酶体增殖物激活受体γ（PPARγ）激动剂进行了研究。在MCF-7乳腺癌细胞中进行的PPARγ依赖性反式激活试验的构效关系研究表明，5-20微摩尔浓度的含对三氟甲基、叔丁基、氰基、二甲基氨基和苯基的化合物具有活性，而对位甲基、氢、甲氧基、羟基或卤素基团作为PPARγ激动剂则无活性。在用PPARγ特异性拮抗剂N-（4'-氨基吡啶基）-2-氯-5-硝基苯甲酰胺共处理的MCF-7细胞中，15-脱氧-Δ12,14-前列腺素J2（PGJ2）和DIM-C-pPhCF(3)诱导的PPARγ依赖性反式激活受到抑制。在哺乳动物双杂交试验中，DIM-C-pPhCF(3)和PGJ2（5-20微摩尔）诱导PPARγ与类固醇受体共激活因子（SRC）1、SRC2（TIFII）和甲状腺激素受体相关蛋白220相互作用，但不与SRC3（AIB1）相互作用。相比之下，DIM-C-pPhCF(3)而非PGJ2诱导PPARγ与PPARγ共激活因子-1相互作用。C-取代二吲哚甲烷可抑制致癌物诱导的大鼠乳腺肿瘤生长，诱导3T3-L1前脂肪细胞分化，抑制MCF-7细胞生长及G(0)/G(1)-S期进程，诱导细胞凋亡，并下调乳腺癌细胞中细胞周期蛋白D1蛋白和雌激素受体α。这些化合物是一类新型合成PPARγ激动剂，在MCF-7细胞中诱导的反应与PGJ2所观察到的反应相似。
