1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes inhibit growth, induce apoptosis, and decrease the androgen receptor in LNCaP prostate cancer cells through peroxisome proliferator-activated receptor gamma-independent pathways.
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)gamma agonists. In LNCaP prostate cancer cells, these compounds induce PPARgamma-dependent transactivation, inhibit cell proliferation, and induce apoptosis. In addition, these PPARgamma 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 PPARgamma 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 PPARgamma-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.
Chintharlapalli
Sudhakar
S
Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Vet. Res. Bldg. 409, College Station, TX 77843-4466, USA.
Papineni
Sabitha
S
Safe
Stephen
S
D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000494:pharmacology*; D051242:Caveolin 1 / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D001555:Benzene Derivatives; D051242:Caveolin 1; D007211:Indoles; D047495:PPAR gamma; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen