The androgen-sensitive human prostate cancer cell line LNCaP expresses the estrogen receptor beta and androgen receptor and can be stimulated by androgens to secrete prostate-specific antigen (PSA). In this study we demonstrate the cancer protective potential of silibinin, a flavolignan derived from the fruits of Silybum marianum, which down-regulates the co-activator of the androgen receptor, the prostate epithelium-derived Ets transcription factor (PDEF) and consequently the secretion of PSA. LNCaP cells were treated with various concentrations of silibinin in the presence or in the absence of 5alpha-dihydrotestosterone (DHT). We used real-time RT-PCR to quantify mRNA expression of PDEF and PSA with gene-specific dual-labelled fluorescence probes. PSA secretion from LNCaP cells in conditioned media was measured with the Elecsys System 2010. Silibinin down-regulated PSA mRNA expression and PSA secretion in conditioned medium under basal and DHT (10(-8) M) stimulated conditions, which was paralleled by PDEF down-regulation. DHT alone stimulated PDEF and PSA gene expression and PSA secretion. The down-regulation of basal as well as DHT stimulated PDEF and PSA by silibinin demonstrates the antiproliferative potential of this agent. These effects underline the possible therapeutic use of silibinin in the management of prostate cancer.