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Transforming growth factor beta 1 transduced mouse prostate reconstitutions: II. Induction of apoptosis by doxazosin
1Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Background:
To study the possible relationship between adrenergic activities and the pathogenesis of benign prostatic hyperplasia (BPH), we tested the effect of doxazosin, an alpha 1-adrenoceptor antagonist, on prostatic growth in vivo using a mouse model for BPH.
Methods:
The mouse prostate reconstitution (MPR) model system with retroviral (BabeTGF-beta 1Neo) transduction of transforming growth factor beta 1 (TGF-beta 1) was used to induce focally hyperplastic BPH-like lesions and increase the number of catecholaminergic neurons. The mice were treated with daily intraperitoneal injections of doxazosin (3 mg/kg).
Results:
Doxazosin caused a significant reduction in the wet weight of BabeTGF-beta 1-infected MPRs. The percent of PCNA-positive epithelial cells was similar in the doxazosin-treated and water only, control groups. There was a significant increase in the number of epithelial cells undergoing programmed cell death, apoptosis, in the doxazosin group (apoptotic index = 4.7 for doxazosin group vs. 3.1 for control group, P < 0.05). The doxazosin-induced apoptosis was more apparent in TGF-beta 1 transduced MPRs than BAG alpha control MPRs, and was not seen in the prostates of the adult male mice into which the MPRs were engrafted.
Conclusions:
Our data demonstrate a novel and potentially important biological activity of doxazosin in vivo in this mouse model of BPH.
Insights
Doxazosin significantly reduced prostate size in a mouse model of benign prostatic hyperplasia (BPH). This alpha-blocker increased apoptosis, or programmed cell death, in prostate cells, suggesting a novel therapeutic effect.
Area of Science:
- Urology
- Pharmacology
- Cell Biology
Background:
- Adrenergic activities may play a role in benign prostatic hyperplasia (BPH) pathogenesis.
- Alpha 1-adrenoceptor antagonists, like doxazosin, are used clinically.
Purpose of the Study:
- To investigate the effect of doxazosin on prostatic growth in a mouse model of BPH.
- To explore the relationship between adrenergic activity and BPH development.
Main Methods:
- Utilized the mouse prostate reconstitution (MPR) model with retroviral transduction of transforming growth factor beta 1 (TGF-beta 1) to induce BPH-like lesions.
- Administered daily intraperitoneal injections of doxazosin (3 mg/kg) to treated mice.
Main Results:
- Doxazosin significantly reduced the wet weight of hyperplastic prostate tissue in the MPR model.
- Increased apoptosis (programmed cell death) was observed in doxazosin-treated prostates.
- The effect of doxazosin on apoptosis was more pronounced in TGF-beta 1-induced lesions.
Conclusions:
- Doxazosin exhibits a novel biological activity in vivo within this BPH mouse model.
- The findings suggest a potential therapeutic role for doxazosin beyond its alpha-blocking effects in BPH treatment.