Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiology.
Finasteride (Fin) and Doxazosin (Dox), alone or in combination, have been widely used in treatment of benign prostatic hyperplasia (BPH) symptoms and recently have been suggested as potential drugs for prostate cancer (PCa)prevention and treatment. However, little is known about the effects of the combination therapy on prostate tissue morphology, physiology and matrix metalloproteinases (MMPs) activity, a special set of enzymes closely related to PCa progression and metastasis. In this study, adult Wistar rats were treated with Fin + Dox (25 mg/kg per day) and the ventral prostate (VP) was excised at days 3 and 30 of treatment to evaluate morphology, cell proliferation, death, transforming growth factor-beta1 (TGF-beta1) protein expression, MMP-2, MMP-9 activities and MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA expression. Fin + Dox treatment induced a transient increase in testosterone (T) plasma concentration and a permanent reduction in dihydrotestosterone (DHT). The VP and epithelial cell proliferation were reduced and the stromal collagen fibre volume fraction and apoptosis of the epithelial cell were increased. Fin + Dox treatment also increased the TGF-beta1 immunoreaction in the epithelium and in the stroma. The mRNAs for MMP-2, TIMPs-1 and -2 expressions after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any of the groups analysed. Fin + Dox treatment for 30 days promoted a decrease in gelatinolytic activity of MMP-2 and an increase in MMP-9. In conclusion, combined treatment with Fin and Dox interferes in the epithelial cell behaviour and in the MMPs activity, potentially via TGF-beta1-mediated and androgen pathways. Our results contribute to a better understanding of the clinical data and also of the molecular mechanisms behind isolated or combined Fin and Dox long-term treatment.
Justulin
Luis A
LA
Department of Cell Biology, University of Campinas (UNICAMP), Institute of Biology, Campinas, SP, Brazil.
Acquaro
Carolina
C
Carvalho
Robson F
RF
Silva
Maeli Dal Pai
MD
Felisbino
Sérgio L
SL
D000728:Androgens / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D017292:Doxazosin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D011467:Prostate / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D011470:Prostatic Hyperplasia / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology
D000728:Androgens; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D013196:Dihydrotestosterone; D019716:Tissue Inhibitor of Metalloproteinase-2; D013739:Testosterone; D018120:Finasteride; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D017292:Doxazosin