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 γ-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 PPAR gamma- dependent transactivation, inhibit cell proliferation, and induce apoptosis. In addition, these PPAR gamma 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 caveolin1. Moreover, the PPAR gamma 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 PPAR gamma- 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.