Intervention of Prostate Cancer by a Flavonoid Antioxidant Silymarin
Abstract
Oncogenic potential of advanced and androgen-independent prostate cancer (PCA) is causally associated with a ligand/receptor autocrine growth loop, e.g. interaction of transforming growth factor a (TGFalpha) and epidermal growth factor receptor (erbB 1). We rationalized that targeting this pathway would be useful for PCA intervention, and showed recently that a flavonoid antioxidant silymarin inhibits erbB 1 activation followed by a G 1 arrest and inhibition of PCA cell growth. Here we did more studies to define cause and effect relationship for the observed effect of silymarin at membrane receptor and cytoplasmic levels. Treatment of LNCaP and DU145 human prostate carcinoma cells with silibinin (the pure form of silymarin) resulted in highly significant inhibition of TGFalpha binding to erbBE 1 receptor and ligand internalization in both dose- and time-dependent manner. Conversely, silibinin does not result in the inhibition of intrinsic tyrosine kinase activity of erbB 1 in both LNCaP and DU 145 cells. The observed inhibitory effect of silymarin on ligand binding to erbB 1 and ligand internalization also resulted in an inhibition of erbB 1 activation followed by its dimerization that leads to activation of downstream mitogenic signaling. These inhibitory effects of silymarin on LNCaP and DU145 cells also corroborate with its inhibitory effect on both cellular and released expression of TGFalpha in these two cell lines. Together these effects of silymarin resulted in a strong inhibition of constitutive MAPK/ERKl/2 activation in both LNCaP and DU145 cells followed by a strong inhibition in their growth. These results suggest that more detailed mechanistic and tumor studies are needed to assess both preventive and interventive effects of silymarin (or silibinin) against human rostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1999
- Accession Number
- ADA383178
Entities
People
- Rajesh Agarwal