Investigation on the anti-angiogenesis effect and mechanism of α1-adrenoceptor antagonist
Date Issued
2009
Date
2009
Author(s)
Liao, Chun-Hou
Abstract
The purpose of this study is comparing the anti-angiogenetic effect of different α1-adrenoceptor antagonists and investigating the possible mechanism of one with greatest potential. e performed in vitro study using primary culture of human umbilical vein endothelial cell (HUVEC), and evaluated the effect of most common used α1-adrenoceptor antagonists, including doxazosin、terazosin、prazosin, and tamsulosin, on HUVECs. Sulforhodamine B (SRB) assays were used to define cell proliferation, and compared the effect of different α1-adrenoceptor antagonists on HUVEC cell proliferation. The concentration of 50% inhibition on cell growth (IC50) was obtained. Our data showed that prazosin (IC50: 6.53 µM) and doxazosin (IC50: 7.6 µM) have greater growth inhibition than terazosin (IC50: 24.62 µM) and tamsulosin (IC50: 25 µM).e further chose prazosin to inveatigate its anti-angiogenetic mechanism. We found that prazosin has significant inhibition on HUVEC cell growth, cell adhesion, and tube formation. In a concentration of 12.5 µM prazosin, growth inhibition was found in 80% of HUVECs. Significant inhibition of cell adhesion and tube formation was found in a concentration of 30 µM and 2.5 µM, respectively.low cytometric analysis showed that prazosin induced an increase of subG1 population in a concentration of 20 µM for 6 hours. Quantified data showed that the increase is time-dependent and concentration-dependent. However, there is no significant G0/G1 or G2/M arrest. Comet assay was used to evaluate single cell DNA damage, but no DNA damage was observed even 40 µM prazosin was used. Loss of mitochondrial membrane potential was found in a concentration of 20 µM prazosin. estern blotting analysis showed a significant decrease of Mcl-1 in a concentration of 20 µM prazosin for 6 hours. Increase of Bad and Bcl-xL was also found. Cytochrome C in cytosol increases in a concentration of 20 µM prazosin for 12 hours. Expression of cleavage of caspase-9、caspase-3, and caspase-7 were also detected by Western immunoblotting.n conclusion, prazosin has greater growth inhibition of HUVEC than other common α1-adrenoceptor antagonists. The pathway of growth inhibition is suggested to be association with intrinsic apoptotic pathway. In addition, adhesion and tube formation of HUVEC are also inhibited by prazosin. We think prazosin may have a potential role in anti-angiogenesis. Although there is still a long distance of prazosin to be used clinically as an anti-angiogenetic medication, using in combination with chemotherapeutic medication or radiation may be a considered way. To evaluate the preventive effect for prostate cancer is another possible consideration.
Subjects
α1-adrenoceptor antagonist
angiogenesis
SDGs
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