Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia.
OBJECTIVE
The molecular mechanisms underlying the therapeutic effect of the alpha1 blocker, doxazosin, on benign prostatic hyperplasia (BPH) are poorly understood. We evaluated the effect of doxazosin on cell proliferation and apoptosis in the prostatic glandular epithelium and stroma of patients with BPH.


METHODS
We examined proliferative and apoptotic activities in prostate specimens of 22 men a mean of 65 years old with BPH before and after doxazosin treatment within the normal therapeutic range. Proliferative and apoptotic indexes were determined using Ki-67 nuclear antigen staining and the terminal transferase end labeling assay, respectively. The smooth muscle cell content in prostatic specimens was identified by smooth muscle alpha-actin, and desmin immunoreactivity and apoptotic indexes were correlated with prostatic stromal tissue regression and improvement in BPH symptoms.


RESULTS
In response to doxazosin treatment there were no significant changes in the kinetics of cell proliferation in the prostatic epithelial or stromal cell population. Mean pretreatment baseline apoptosis was 1.9 and 1.0% for the epithelial and stromal prostate components, respectively. Mean apoptotic indexes significantly increased after 3 months of doxazosin treatment in the glandular epithelial (6%) and smooth muscle cells (15%). By 12 months after treatment epithelial apoptosis had decreased to constitutive levels, while the apoptotic index of prostatic stroma cells remained high. Doxazosin induced smooth muscle cell apoptosis correlated with prostatic stromal degeneration, decreased alpha-smooth muscle actin expression and improved BPH symptoms.


CONCLUSIONS
These findings implicate the induction of prostate apoptosis by doxazosin as a potential molecular mechanism underlying the acute and chronic therapeutic responses of BPH to alpha1 blockade.
Kyprianou
N
N
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore 21201, USA.
Litvak
J P
JP
Borkowski
A
A
Alexander
R
R
Jacobs
S C
SC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D017292:Doxazosin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology
D000317:Adrenergic alpha-Antagonists; D017292:Doxazosin