Anti-Angiogenic Effects and Mechanism of Prazosin

BACKGROUND. Alpha1-adrenoceptors antagonists (doxazosin, terazosin, prazosin) are commonly prescribed for benign prostate hyperplasia and hypertension. Doxazosin and terazosin exhibit anti-angiogenic effects and apoptotic activities against multiple cell types and are potential preventive agents for prostate cancer. Prazosin induces apoptosis in three prostate cancer cell lines. We hypothesized that prazosin, a more potent alpha1-adrenoceptor antagonist with a distinct mechanism, exhibits anti-angiogenic activity. METHODS. We examined the effect of prazosin on growth and tube formation of human umbilical vascular endothelial cells (HUVECs). We used flow cytometry to assess the effect of prazosin on cell cycle progression and Western blotting to assess its effect on the expression of various apoptotic proteins. RESULTS. Prazosin inhibited the growth of HUVEC with an IC50 of 6.53 mu M and suppressed tube formation in a dose-dependent manner. Unlike prostate cancer cells, prazosin did not arrest cell cycle progression at the G2/M checkpoint. We used rhodamine 123 staining to show that prazosin (20 mu M) treatment induced a loss of mitochondrial membrane potential by 12 hr. Prazosin treatment of HUVECs resulted in reduced MCL-1 expression, increased Bad, and Bcl-xL expression, cytochrome c release, and induction of apoptosis via the intrinsic apoptosis pathway. Prazosin induced apoptosis in prostate cancer cells and normal HUVEC cells via different mechanisms. CONCLUSIONS. These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type. Prostate 71: 976-984, 2011. (C) 2010Wiley-Liss, Inc.