Co-administration of finasteride and the pure anti-oestrogen ICI 182,780 act synergistically in modulating the IGF system in rat prostate.
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.
Huynh
H
H
Molecular Endocrinology Laboratory, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610. cmrhth@nccs.com.sg
Alpert
L
L
Alaoui-Jamali
M A
MA
Ng
C Y
CY
Chan
T W
TW
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
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