Abstract
1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) containing para-trifluoromethyl, t-butyl, and phenyl groups are a novel class of peroxisome proliferator-activated receptor (PPAR)γ agonists. In LNCaP prostate cancer cells, these compounds induce PPARγ-dependent transactivation, inhibit cell proliferation, and induce apoptosis. In addition, these PPARγ agonists modulate a number of antiproliferative and proapoptotic responses, including induction of p27, activating transcription factor 3, and nonsteroidal anti-inflammatory drug-activated gene-1 and down-regulation of cyclin D1 and caveolin-1. Moreover, the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) does not inhibit these effects. The C-DIM compounds also abrogate androgen receptor (AR)-mediated signaling and decrease prostate-specific antigen (PSA) and AR protein expression, and these responses were PPARγ-independent. The effects of C-DIMs on AR and PSA were due to decreased AR and PSA mRNA expression in LNCaP cells. Thus, this series of methylene-substituted diindolylmethane derivatives simultaneously activate multiple pathways in LNCaP cells, including ablation of androgen-responsiveness and down-regulation of caveolin-1. Both of these responses are associated with activation of proapoptotic pathways in this cell line.
Footnotes
-
This study was supported by National Institutes of Health Grants ES09106 and CA112337 and the Texas Agricultural Experiment Station.
-
ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; CDDO, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; DIM-C-pPhC6H5, 1,1-bis(3′-indolyl)-1-(p-phenyl)methane; DIM-C-pPhCF3, 1,1-bis(3′-indolyl)-1-(p-trifluoromethyl)methane; DIM-C-pPhtBu, 1,1-bis(3′-indolyl)-1-(p-t-butyl)methane; DIM-C-pPhOCH3, 1,1-bis(3′-indolyl)-1-(p-methyl)methane; DIM-C-pPhOH, 1,1-bis(3′-indolyl)-1-(p-hydroxyl)methane; C-DIMs, 1,1-bis(3′-indolyl)-1-(p-substitutedphenyl)methanes; NAG-1, nonsteroidal anti-inflammatory drug activated gene-1; AR, androgen receptor; PSA, prostate-specific antigen; FBS, fetal bovine serum; luc, luciferase; ERK, extracellular signal-regulated kinase; ATF3, activating transcription factor 3; EGR-1, early growth response factor 1; PPRE, peroxisome proliferator response element; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; TBST, Tris-buffered saline/Tween 20; BLOTTO, bovine lacto transfer optimizer; PCR, polymerase chain reaction; DHT, dihydrotestosterone; PI3K, phosphatidylinositol-3-kinase; PCK, protein kinase C; GF109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; PD98059, 2′-amino-3′-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; GW9662, 2-chloro-5-nitrobenzanilide; SP600125, 1,9-pyrazoloanthrone.
-
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received July 7, 2006.
- Accepted November 8, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
