Drugs online research references
J Urol. 2003 Feb;169(2):724-9.
Identification of apoptotic and antiangiogenic activities of terazosin in human prostate cancer and endothelial cells.
Pan SL, Guh JH, Huang YW, Chern JW, Chou JY, Teng CM.
Pharmacological Institutes, School of Pharmacy and Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
PURPOSE: 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. MATERIALS AND 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.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12544352&dopt=Abstract
utmb.edu
Much of the acute cutaneous neurogenic inflammation after intradermal injection of capsaicin (CAP) in rats is mediated by dorsal root reflexes (DRRs), which cause the release of inflammatory agents from primary afferent terminals. Sympathetic efferents modulate neurogenic inflammation by interaction with primary afferent terminals. In this study, we examined if DRR-mediated flare after CAP injection is subject to sympathetic modulation. Changes in cutaneous blood flow on the plantar surface of the foot were measured using a laser Doppler flow meter. After CAP injection, cutaneous flare spread more than 20 mm away from the site of CAP injection. However, this CAP-induced flare was significantly reduced after surgical sympathectomy. Decentralization of postganglionic neurons did not affect the flare induced by CAP injection. If the foot of sympathectomized rats was pretreated with an alpha(1)-adrenoceptor agonist (phenylephrine) by intra-arterial injection, the spread of flare induced by CAP injection could be restored. However, if the spinal cord was pretreated with a GABA(A) receptor antagonist, bicuculline, to prevent DRRs, phenylephrine no longer restored the CAP-evoked flare. An alpha(2)-adrenoceptor agonist (UK14,304) did not affect the CAP-evoked flare in sympathectomized rats. In sympathetically intact rats, blockade of peripheral alpha(1)-adrenoceptors with terazosin profoundly reduced the flare induced by CAP injection, whereas blockade of peripheral alpha(2)-adrenoceptors by yohimbine did not obviously affect the flare. Therefore the pathogenesis of acute neurogenic inflammation in the intradermal CAP injection model depends in part on intact sympathetic efferents and alpha(1)-adrenoceptors. Peripheral alpha(1)-adrenoceptors thus modulate the ability of capsaicin sensitive afferents to evoke the release of inflammatory agents from primary afferents by DRRs.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12574463&dopt=Abstract
J Urol. 2003 Mar;169(3):1150-6.
Anoikis induction by quinazoline based alpha 1-adrenoceptor antagonists in prostate cancer cells: antagonistic effect of bcl-2.
Keledjian K, Kyprianou N.
Divisionof Urology, University of Maryland, Baltimore, USA.
PURPOSE: The ability of the quinazoline derived alpha1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in benign and malignant prostate cells has been established. In this study we investigated the effect of the 2 piperazidinyl quinazoline based alpha1-adrenoceptor antagonists and the methoxybenzene sulfonamide alpha1-antagonist tamsulosin on human prostate cancer cell adhesion. MATERIALS AND METHODS: Androgen independent PC-3 prostate cancer cells and PC-3 transfectant clones over expressing the apoptosis suppressor bcl-2 were used as an in vitro model. Cells were treated with pharmacologically relevant doses of 1 of the 3 alpha1-adrenoceptor antagonists and the effect on cell viability/cell adhesion on various substrates was examined. Analysis of expression of key attachment factors, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-alpha, was performed. RESULTS: Our results indicate a significant decrease in prostate cancer cell adhesion to gelatin and collagen but not to fibronectin in prostate cancer cells treated with doxazosin or terazosin (25 microM.) compared with untreated control cultures (p <0.05). In contrast, tamsulosin had no effect on prostate cancer cell adhesion. The 2 quinazolines doxazosin and terazosin but not tamsulosin had a significant inhibitory effect on prostate tumor cell invasion. In bcl-2 over expressing prostate cancer cells there was significant suppression of doxazosin induced anoikis and cell invasion compared with neocontrol transfectants (p <0.05). Doxazosin resulted in transient down-regulation (2-fold decrease) of VEGF at the mRNA and protein levels, as detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. No significant changes in the expression profile of hypoxia inducible factor-1 alpha were observed after treatment with quinazolines. Furthermore, bcl-2 resulted in partial reversion of the doxazosin induced VEGF decrease. CONCLUSIONS: These findings demonstrate that the quinazoline derived alpha1-antagonists doxazosin and terazosin but not sulfonamide based tamsulosin induce anoikis and inhibit prostate cancer cell invasion, an effect that is antagonized by bcl-2. This molecular basis of an alpha1-adrenoceptor independent action against prostate cancer cells by the quinazolines may have potential therapeutic significance in prostate cancer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12576871&dopt=Abstract
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