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Br J Cancer. 2003 May 19;88(10):1615-21.
Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.

Partin JV, Anglin IE, Kyprianou N.

Division of Urology, Department of Surgery, University of Kentucky Medical Center, Lexington, KY 40536, USA.

Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771931&dopt=Abstract

rush.edu

The purpose of this paper is to review the role of doxazosin, a long-acting alpha(1)-blocker, as a component of combination therapy for patients with stage 1 and stage 2 hypertension and for patients with concomitant hypertension and hyperlipidemia or glucose intolerance. Recent studies that evaluated doxazosin as combination therapy in the treatment of patients with inadequately controlled hypertension and patients with concomitant hypertension and other disorders were reviewed. Data extraction was based on the tolerability and efficacy data of doxazosin in patients with hypertension. Compared with placebo, doxazosin combination therapy leads to significant improvements in sitting and standing blood pressure. Doxazosin is well tolerated, with only minor adverse effects (e.g., headache, dizziness) as the most commonly reported treatment-related complications. The studies described demonstrate that doxazosin is effective as combination therapy for patients with stage 1 and stage 2 hypertension. The positive effects of doxazosin on serum lipids make combination therapy with doxazosin an attractive treatment option for patients who have concomitant hyperlipidemia or glucose intolerance.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12775963&dopt=Abstract [PubMed - in process]




Naunyn Schmiedebergs Arch Pharmacol. 2003 Jul;368(1):49-56. Epub 2003 Jun 25.
Pharmacological characterization of unique prazosin-binding sites in human kidney.

Hiraoka Y, Taniguchi T, Tanaka T, Okada K, Kanamaru H, Muramatsu I.

Department of Pharmacology, School of Medicine, Fukui Medical University, 910-1193 Matsuoka, Fukui, Japan.

In human kidney, we found unique prazosin-binding sites that were insensitive to phentolamine and were thus unlikely to be alpha(1)-adrenoceptors.As the binding of [(3)H]prazosin to phentolamine-insensitive sites was prevented by 100 microM guanabenz, the insensitive sites were evaluated by subtracting [(3)H]prazosin binding in the presence of 100 microM guanabenz from that in the presence of 10 microM phentolamine. [(3)H]Prazosin bound to the phentolamine-insensitive sites monophasically with a high affinity (pK(d); 9.1+/-0.08, n=8), and the B(max) value (814+/-204 fmol mg(-1) protein, n=8) was more than ten times that of the phentolamine-sensitive alpha(1)-adrenoceptor (pK(d)=9.9+/-0.13, B(max)=66+/-23 fmol mg(-1) protein, n=7). The phentolamine-insensitive sites in human kidney were highly sensitive to other quinazoline derivatives such as terazosin and doxazosin. However, other alpha(1)-adrenoceptor antagonists (tamsulosin, WB4101 and corynanthine) did not inhibit the binding at a range of concentrations that generally exhibit alpha(1)-adrenoceptor antagonism, and noradrenaline, rauwolscine and propranolol were without effect on the [(3)H]prazosin binding. On the other hand, ligands for the renal Na(+)-transporter (amiloride and triamterene) and for imidazoline recognition sites (guanabenz, guanfacine and agmatine) displaced the binding of [(3)H]prazosin to phentolamine-insensitive sites at micromolar concentrations. Photoaffinity labeling with [(125)I]iodoarylazidoprazosin showed phentolamine-insensitive labeling at around 100 kDa, a molecular size larger than that of human alpha(1a)- and alpha(1b)-adrenoceptors expressed in 293 cells (50-60 and 70-80 kDa, respectively) on electrophoresis. In contrast, there was no detectable phentolamine-insensitive binding site but were phentolamine-sensitive alpha(1)-adrenoceptors in human liver (pK(d)=10.0+/-0.06, B(max)=44+/-6 fmol mg(-1) protein, n=3). Phentolamine-insensitive prazosin binding sites were also detected in rabbit kidney (approximately 50% of specific binding sites) but were minor in rat kidney (less than 20%).In conclusion, there are unique prazosin-binding sites in human kidney, the pharmacological profiles of which were distinct from those of known adrenoceptors.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12827214&dopt=Abstract [PubMed - in process]





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