title: Co-administration of finasteride and the pure anti-oestrogen ICI 182,780 act synergistically in modulating the IGF system in rat prostate.
abstract: Prostate cancer is the most diagnosed invasive malignancy in males. Androgens and oestrogens have been implicated in the pathogenesis of prostate cancer. We report herein that the pure anti-oestrogen ICI 182,780 (ICI) reduces Ki-67 labelling index and IGF-I receptor levels in rat prostate. Increase of IGF-I mRNA and IGF-binding protein 3 (IGFBP-3) accumulation occur without any effect on prostate weight. Finasteride significantly decreases prostate weight and inhibits IGF-I gene expression. IGFBP-3 mRNA, Akt and phospho-Akt are not affected by finasteride. Co-administration of ICI plus finasteride reduces prostate weight by approximately 50% and causes acinar dilation with decreased luminal epithelial cell thickness. The acinar epithelial cells became atrophic and inactive with minimal cytoplasm. We also demonstrate a synergistic effect of ICI and finasteride on induction of IGFBP-3 accumulation and inhibition of Akt phosphorylation. Because the IGF and IGFBP-3 system plays an important role in prostate epithelial cell proliferation, apoptosis and tumour progression, the inhibitory effects of finasteride and ICI on IGF system may contribute to their anti-proliferative activity. These observations support a potential use of ICI in conjunction with finasteride in the prevention and/or treatment of prostate cancer.
authors.affiliation: Molecular Endocrinology Laboratory, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610. cmrhth@nccs.com.sg
authors.forename: H
authors.initials: H
authors.lastname: Huynh
authors.forename: L
authors.initials: L
authors.lastname: Alpert
authors.forename: M A
authors.initials: MA
authors.lastname: Alaoui-Jamali
authors.forename: C Y
authors.initials: CY
authors.lastname: Ng
authors.forename: T W
authors.initials: TW
authors.lastname: Chan
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D000077267:Fulvestrant; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D018972:Insulin-Like Growth Factor Binding Protein 3; D011518:Proto-Oncogene Proteins; D000077267:Fulvestrant; D004958:Estradiol; D018120:Finasteride; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt