Induction of apoptosis in rat ventral prostate by finasteride is associated with alteration in MAP kinase pathways and Bcl-2 related family of proteins.
Finasteride is widely used in treatment of symptomatic benign prostatic hyperplasia. Treatment of rats with finasteride caused a significant decrease in ventral prostate weight and intraprostatic dihydrotestosterone levels while intraprostatic testosterone levels were increased. Finasteride inhibited Akt-1 and MAPK expression while expression of PTEN was significantly increased only at 100 mg dose. Basal phosphorylation of c-Raf, MEK1/2, MAPK and the transcription factor Elk-1 was significantly reduced by finasteride. The rate of prostate epithelial apoptosis is equivalent to 0.1+/-0.03, 0.6+/-0.18%, 0.92+/-0.24% and 1.42+/-0.3% on treatments with 0, 1, 10 and 100 mg finasteride per kg body weight, respectively. Concomitantly, these treatments led to a 2.5-, 4.0- and 4.0-fold increase in Bad while a slight decrease in Bax was observed. Similar elevations were also observed in Bcl-xs levels which increased by 9.8-, 10- and 12-fold respectively in the finasteride treatments as compared to controls. Bcl-xL levels in ventral prostates treated with 1, 10 and 100 mg finasteride were approximately 30, 30 and 26% of control, respectively. Significant reduction in Bcl-2 expression was observed only at the dose of 100 mg/kg body weight. These findings suggest that modulation of MAP kinase and Akt expression, Bcl-xL, Bcl-xs, Bcl-2 and Bad proteins by finasteride may be, in part, responsible for the anti-proliferative and apoptotic effect of this drug seen clinically and in animal models.
Huynh
Hung
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610. cmrhth@nccs.com.sg
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D042944:Cholestenone 5 alpha-Reductase; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000502:physiology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D042944:Cholestenone 5 alpha-Reductase; D004791:Enzyme Inhibitors; D018120:Finasteride; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D010088:Oxidoreductases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; C494920:Akt1 protein, rat