Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells

Silibinin, a naturally occurring flavonoid antioxidant found in the milk th istle, has recently been shown to have potent antiproliferative effects aga inst various malignant cell lines, but the underlying mechanism of action r emains to be elucidated, We investigated the effect of silibinin on androge n-independent prostate cancer PC-3 cells. At pharmacologically achievable s ilibinin concentrations (0.02-20 muM), we observed increased insulin-like g rowth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditio ned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9 -fold increase over baseline at 20 muM silibinin, An IGFBP-3 antisense olig odeoxynucleotide that attenuated silibinin-indnced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin, We also observed that silibinin reduced insulin receptor substrate 1 tyros ine phosphorylation, indicating an inhibitory effect on the insulin-like gr owth factor I receptor-mediated signaling pathway, These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and j ustify further work to investigate potential use of this compound or its de rivatives in prostate cancer treatment and prevention.