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.