Identification of apoptotic and antiangiogenic activities of terazosin in human prostate cancer and endothelial cells.
OBJECTIVE
It has been suggested that terazosin has an inhibitory effect on prostate tumor growth. We determined if terazosin action contributes to direct suppression of the angiogenic effect.


METHODS
PC-3 cells and primary cultures of human benign prostatic cells were used in this study. The cytotoxic effect was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase release reaction. The in vivo angiogenic effect was determined in nude mice models, followed by histological examination and quantification by the hemoglobin detection assay. In vitro determination of cell migration, proliferation and tube formation was performed in cultured human umbilical vein endothelial cells. RESULTS Terazosin induced cytotoxicity in PC-3 and human benign prostatic cells with an IC50 of more than 100 microM. The positive terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and lactate dehydrogenase release reaction was associated with terazosin induced cytotoxicity, indicating apoptotic and necrotic cell death. Furthermore, cytotoxicity due to terazosin action was not a common characteristic of a quinazoline based structure. Terazosin significantly inhibited vascular endothelial growth factor induced angiogenesis in nude mice with an IC50 of 7.9 microM., showing that it had a more potent anti-angiogenic than cytotoxic effect. Terazosin also effectively inhibited vascular endothelial growth factor induced proliferation and tube formation in cultured human umbilical vein endothelial cells (IC50 9.9 and 6.8 microM., respectively).


CONCLUSIONS
Together our data suggest that terazosin shows direct anti-angiogenic activity through the inhibition of proliferation and tube formation in endothelial cells. This action may partly explain the in vivo antitumor potential of terazosin.
Pan
Shiow-Lin
SL
Pharmacological Institutes, School of Pharmacy and Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Guh
Jih-Hwa
JH
Huang
Ying-Wen
YW
Chern
Ji-Wang
JW
Chou
Jui-Yi
JY
Teng
Che-Ming
CM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014407:Tumor Cells, Cultured
C041226:Terazosin; D011224:Prazosin