Co-administration of finasteride and the pure anti-oestrogen ICI 182,780 act synergistically in modulating the IGF system in rat prostate

• Published in: Journal of endocrinology Vol. 171; no. 1; pp. 109 - 118
• Main Authors: Huynh, H, Alpert, L, Alaoui-Jamali, MA, Ng, CY, Chan, TW
• Format: Journal Article
• Language: English
• Published: Colchester BioScientifica 01.10.2001; Portland Press
• Subjects: 5-alpha Reductase Inhibitors; Animals; Biological and medical sciences; Blotting, Northern - methods; Cell Division - drug effects; Drug Synergism; Enzyme Inhibitors - pharmacology; Epithelial Cells - drug effects; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Finasteride - pharmacology; Fulvestrant; Hormones. Endocrine system; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-Like Growth Factor I - metabolism; Male; Medical sciences; Organ Size - drug effects; Pharmacology. Drug treatments; Phosphorylation; Prostate - anatomy & histology; Prostate - drug effects; Prostate - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Receptor, IGF Type 1 - metabolism; Statistics, Nonparametric; Drug combination; Finasteride; Rat; Rodentia; Antiestrogen; Antiandrogen; Antihormone; Azasteroid; Biological activity; Vertebrata; Insulin like growth factor; Mammalia; Animal; Urogenital system; Prostate
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/joe.0.1710109

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.