Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three hundred and fifty-three patients with symptomatic benign prostatic hyperplasia were randomized to doxazosin or placebo, with morning or evening dosing, to compare the effect of dosing time on the efficacy and safety of doxazosin treatment. After 24 weeks of treatment, the mean International Prostate Symptom Score had decreased by 6.8 units in the doxazosin group compared with 4.5 units in the placebo group (P=0.003). Improvements in Q(max) of 2.03 ml/s and 0.30 ml/s were seen for the doxazosin and the placebo groups, respectively (P<0.001). No differences in efficacy or safety between the morning- and evening-dosed subgroups were observed. Doxazosin was significantly more effective than placebo at improving symptoms of BPH and urinary flow rates at endpoint, and was well tolerated. The time of dosing did not appear to influence the efficacy or safety of doxazosin, suggesting that there is no need to restrict administration of doxazosin to the evening in BPH patients.
Prostate Cancer Prostatic Dis 1998 Mar
PMID:Morning vs evening dosing with doxazosin in benign prostatic hyperplasia: efficacy and safety. 1249 11

The quinazoline family of alpha1-blockers (prazosin, doxazosin, and terazosin) induce apoptosis of prostate cells through an alpha1-adrenoceptor-independent mechanism. The objective of this study was to gain insight into the non-adrenergic, apoptotic mechanism of action of doxazosin in the prostate and the induction of anoikis by doxazosin. Primary cultures of benign prostate stromal and epithelial cells and the LNCaP (androgen sensitive) and PC-3 (androgen insensitive) prostate carcinoma cell lines were treated with doxazosin (0-50 microM). The effects of doxazosin on cell morphology, caspase-3 activity, and the expression levels of focal adhesion kinase (FAK) and integrin-linked kinase (ILK) were examined. Doxazosin induced changes in morphology consistent with anoikis in both benign and cancerous prostatic cells and increased caspase-3 activity. The effects were similar comparing benign cells (which express alpha1-adrenoceptors) and cancer cells (which do not express alpha1-adrenoceptors), but were more robust in benign cells. Norepinephrine had no effect on doxazosin-induced cell morphology or caspase-3 activity. Treatment of PC-3 cells with doxazosin significantly reduced the protein levels of FAK but did not significantly affect the levels of ILK. These findings suggest that doxazosin induces apoptosis and anoikis of prostate cancer cells by a mechanism of action that is alpha1-adrenoceptor independent. The apoptosis of cancer cells induced by doxazosin counteracts cell proliferation and may have the potential of retarding or reversing prostate cancer cell growth.
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PMID:Induction of anoikis by doxazosin in prostate cancer cells is associated with activation of caspase-3 and a reduction of focal adhesion kinase. 1522 Dec 43

The quinazoline-derived alpha1-adrenoceptor antagonists, doxazosin and terazosin have been recently shown to induce an anoikis effect in human prostate cancer cells and to suppress prostate tumor vascularity in clinical specimens [Keledjian and Kyprianou, 2003]. This study sought to examine the ability of doxazosin to affect the growth of human vascular endothelial cells and to modulate vascular endothelial growth factor (VEGF)-mediated angiogenesis. Human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to determine the effect of doxazosin on cell growth, apoptosis, adhesion, migration, and angiogenic response of endothelial cells. The effect of doxazosin on cell viability and apoptosis induction of human endothelial cells, was evaluated on the basis of trypan blue and Hoechst 33342 staining, respectively. Doxazosin antagonized the VEGF-mediated angiogenic response of HUVEC cells, by abrogating cell adhesion to fibronectin and collagen-coated surfaces and inhibiting cell migration, via a potential downregulation of VEGF expression. Furthermore there was a significant suppression of in vitro angiogenesis by doxazosin on the basis of VEGF-mediated endothelial tube formation (P < 0.01). Fibroblast growth factor-2 (FGF-2) significantly enhanced HUVEC cell tube formation (P < 0.01) and this effect was suppressed by doxazosin. These findings provide new insight into the ability of doxazosin to suppress the growth and angiogenic response of human endothelial cells by interfering with VEGF and FGF-2 action. This evidence may have potential therapeutic significance in using this quinazoline-based compound as an antiangiogenic agent for the treatment of advanced prostate cancer.
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PMID:Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion. 1552 77

We have studied the efficacy of Alfa-blockade with Doxazosin vs Tamsulozin in combination with Intermittent Androgen Blockade (IAB) in patients with low grade prostate cancer. Our clinical trial included: I group (n=15) of patients who received doxazosin with IAB and flutamide; II group (n=13) of patients who received tamsulozin in combination with IAB and flutamide and III (n=33) group with flutamid monotherapy alone. Our results have shown that the combination of doxasozin and IAB with the flutamide leads to the better improvement of uroflowmetry and IPSS parameters, whereas the tamsulozin and IAB with flutamide combination induce those improvements for the longer period during the disease remission.
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PMID:[Alfa-blockade with doxazosin vs tamsulozin in combination of intermittent androgen blockade in patients with prostate cancer]. 1585 91

Maspin is a mammary serine protease inhibitor or serpin with tumor suppressive and antiangiogenic activity that inhibits tumor motility, invasion and metastasis, at least by its actions on cell membrane and extracellular matrix (ECM) proteins. Previous studies documented that the quinazoline-derived alpha1-adrenoceptor antagonist doxazosin affects the attachment and migration of prostate cancer cells. In this study, we investigated the effect of maspin overexpression on the apoptotic/antiadhesion response of prostate cancer cells to doxazosin. The response of maspin-overexpressing clones of human prostate cancer cells DU-145 to doxazosin was evaluated by determining cell viability, apoptosis and cell proliferation on the basis of the trypan blue exclusion assay/methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, Hoechst staining and caspase-3 activation, and [(3)H]thymidine incorporation assay. Vascular endothelial growth factor (VEGF), transforming growth factor betaRII (TGFbetaRII), Smad4 (a TGFbeta intracellular effector) and bax expression was evaluated at the mRNA and protein level using reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The effect of doxazosin on cell attachment of maspin-expressing prostate cancer cells was evaluated on collagen- and fibronectin-coated plates. Cell migration was assessed using the wounding assay. In response to tumor necrosis factor-related apoptosis-inducing ligand, DU-145-maspin expressing cells undergo apoptosis, via poly(ADP-ribose) polymerasecleavage and caspase-3 activation. DU-145-maspin cells exhibited higher sensitivity to doxazosin and an earlier temporal activation of caspase-3. The number of apoptotic cells detected in response to doxazosin was significantly higher compared to the neo control (P<0.0001). Doxazosin resulted in dramatic downregulation of the 189 isoform of VEGF in maspin transfectants, while a fivefold induction of Smad4 mRNA expression was detected in those cells after 24 h of treatment. Maspin overexpression in prostate cancer cells resulted in an increased ability to attach to ECM-coated plates, and doxazosin treatment considerably antagonized this effect by decreasing the attachment potential to collagen and fibronectin. The present study supports the ability of maspin to enhance the apoptotic threshold of prostate cancer cells to the quinazoline-based alpha1-adrenoceptor antagonist doxazosin. These findings may have therapeutic significance in the development of antiangiogenic targeting by doxazosin and derivative agents for advanced prostate cancer.
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PMID:Maspin sensitizes prostate cancer cells to doxazosin-induced apoptosis. 1600 19

Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective alpha(1)-adrenergic receptor antagonist, used to treat hypertension, also inhibits prostate cancer cell proliferation. We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G(0)-G(1) cell cycle arrest, and reduced phosphorylated retinoblastoma levels. In addition, increased annexin-fluorescein isothiocyanate immunoreactivity and cleaved caspase-3 levels, in keeping with dox-mediated apoptosis, were observed in the human and murine pituitary tumor cells, and dox administration to mice, harboring corticotroph tumors, decreased tumor growth and reduced plasma ACTH levels. dox-mediated antiproliferative and proapoptotic actions were not confined to alpha-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the alpha-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory kappaB (IkappaB)-alpha expression, and nuclear factor-kappaB transcription and decreased basal and TNFalpha-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective alpha(1)-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its alpha-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-kappaB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.
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PMID:Alpha1-adrenergic receptor antagonists: novel therapy for pituitary adenomas. 1602 Apr 84

Doxazosin is a quinazoline-based compound acting as an alpha-1-adrenergic inhibitor shown to induce apoptosis in prostate cancer cell lines via an alpha-1-adrenergic receptor-independent mechanism. To better understand the mechanism of doxazosin-induced apoptosis in prostate cancer, we performed cDNA microarray to analyze gene expression changes produced by doxazosin in the androgen-dependent human prostate cancer cell line, LNCaP. We found that 70 and 92 genes were deregulated after 8 and 24 h of doxazosin treatment, respectively. These genes are involved in several cellular processes such as cell-cycle regulation, cell adhesion and signal transduction pathways. Strikingly, we found that doxazosin induces deregulation of genes implicated in DNA replication and repair, such as GADD45A, XRCC5 and PRKDC. These facts, together with the demonstration of the ability of doxazosin to bind DNA, allowed us to propose a novel mechanism of action for doxazosin in prostate cancer cells that implies DNA-damage mediated apoptosis by down-regulation of XRCC5 and PRKDC genes.
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PMID:Doxazosin induces apoptosis in LNCaP prostate cancer cell line through DNA binding and DNA-dependent protein kinase down-regulation. 1627 18

Quinazoline-based alpha1-adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an alpha1-adrenoceptor-independent pathway, involving activation of transforming growth factor-beta1 (TGF-beta1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 micromol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins alpha2, alphaV, beta1, and beta8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in doxazosin-induced apoptosis. The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of doxazosin in prostate cells. These results show that doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor-mediated mechanism with a potential integrin contribution towards cell survival outcomes.
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PMID:Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway. 1639 62

Doxazosin triggers apoptosis via an imprecisely defined receptor mechanism that is related to tumor necrosis factor receptors (TNFRs). The aim of this study was to determine CD95, TNFR-1, TNFR-2, CD40 expression in primary prostate epithelial cultures incubated with doxazosin. Epithelial cultures were cultivated from 10 benign prostate hyperplasia patients. The cells were incubated with 20, 50 and 80 microM of doxazosin. Apoptosis was confirmed by fluorescence microscopy and flow cytometry. The cells were analyzed for expression of FAS, CD40, TNFR-1 and TNFR-2 by flow cytometry. Early apoptotic cells were present in all groups. A positive correlation was noticed between doxazosin dose and TNFR-1-, -2-positive cells. A decrease of CD40-positive cell population was observed in the lowest concentration. A decrease of mean fluorescence intensity signal of CD40 and CD95 was observed in the lowest concentration. Doxazosin-triggered apoptosis was dose-independent. The initiation of apoptosis was a result of receptors 'crosstalk' rather than a single receptor pathway activation. TNF receptor self-assembly process should be checked as a potential mechanism leading to apoptosis after doxazosin treatment.
Prostate Cancer Prostatic Dis 2008
PMID:The influence of alpha1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients. 1753 95

The selective alpha(1)-adrenergic receptor antagonist doxazosin (dox) has been reported to inhibit prostate cancer proliferation. We now demonstrate that dox-treatment inhibits proliferation and induces apoptosis in breast cancer cells in vitro by mechanisms that do not wholly involve the alpha1-adrenergic receptor. Intriguingly, dox-treatment reduced phosphorylated EGFR expression, decreased pERK1/2 levels and decreased NF-kappaB, AP-1, SRE, E2F and CRE-mediated transcriptional activity. EGF- and TNFalpha treatment alone failed to block dox-mediated breast cancer apoptotic effects, but combination of EGF and TNFalpha treatments completely abrogated dox-induced breast cancer cell apoptosis, indicating doxazosin inhibits both EGFR and NF-kappaB signalling pathways to induce breast cancer cell apoptosis. Doxazosin is proposed as a possible novel medical therapy for breast cancer.
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PMID:The alpha1-adrenergic receptor antagonist doxazosin inhibits EGFR and NF-kappaB signalling to induce breast cancer cell apoptosis. 1804 75


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