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Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both drugs, already in clinical use and with established adverse-effect profiles, against prostatic tumors for the treatment of advanced prostate cancer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10969806&dopt=Abstract
nifty.ne.jp
The role of spinal alpha(1)-adrenergic mechanisms in the control of urinary bladder function was examined in urethane (1.2 g/kg s.c.) anesthetized and decerebrate unanesthetized female Sprague-Dawley rats (250-320 g). Bladder activity was recorded via a transurethral catheter during continuous infusion (0.21 ml/min) cystometrograms or under isovolumetric conditions. All drugs were administered intrathecally at the L(6)-S(1) segmental level of spinal cord. During cystometrograms, 3 or 30 nmol of phenylephrine (alpha(1)-adrenergic agonist) did not alter bladder activity; whereas 300 nmol increased the intercontraction interval by 98% and pressure threshold for inducing micturition by 115%, but did not change bladder contraction amplitude. A large dose of phenylephrine (3000 nmol) completely blocked reflex voiding and induced overflow incontinence at a high baseline pressure (mean: 33 cmH(2)O; range: 28-42 cmH(2)O). Under isovolumetric conditions, 3-30 nmol of phenylephrine abolished bladder activity for 22-45 min; whereas smaller doses (0.003-0.3 nmol) were inactive. Doxazosin (50 nmol), an alpha(1)-adrenergic antagonist, decreased intercontraction intervals but did not change bladder contraction amplitude during cystometrograms. Under isovolumetric conditions this dose of doxazosin increased bladder contraction frequency and decreased bladder contraction amplitude. Smaller doses (5 or 25 nmol) of doxazosin did not alter bladder activity. These studies suggest that two types of spinal alpha(1)-adrenergic mechanisms are involved in reflex bladder activity: (1) inhibitory control of the frequency of voiding reflexes presumably by regulating afferent processing in the spinal cord and (2) facilitatory modulation of the descending limb of the micturition reflex pathway.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056182&dopt=Abstract
Prostate Suppl. 2000;9:34-41.
Effects of alpha1-adrenoceptor antagonists on cultured prostatic smooth muscle cells.
Boesch ST, Dobler G, Ramoner R, Corvin S, Thurnher M, Bartsch G, Klocker H.
Department of Urology, University of Innsbruck, Innsbruck, Austria.
BACKGROUND: alpha1-adrenoceptor (alpha1-AR) antagonists, used to relieve the lower tract urinary symptoms (LUTS) in benign prostate hyperplasia (BPH) patients, are thought to act in inhibiting the contraction of stromal smooth muscle. An attempt was made using new technology to visualize and quantify the effect of alpha1-AR antagonists in a cell culture model of prostatic smooth muscle cells (SMC). METHODS: Prostatic smooth muscle cells cultured from human prostate tissue were treated with alpha1-AR agonists and antagonists. The effects on cell growth, cell contraction, differentiation status, and apoptosis were determined by means of an MTT cell viability assay, time-lapse video microscopy, RT-PCR analysis, and FACS analysis of annexin V/propidium iodide-stained cells, respectively. RESULTS: Prostatic smooth muscle cells derived from prostate tissue expressed SMC-specific markers. They showed spontaneous contractions, and phenylephrine increased the percentage of contracting cells by 3-fold. alpha1-AR antagonists inhibited spontaneous as well as phenylephrine-induced contractions. Long-term treatment with doxazosin induced differentiation tended towards a contractile phenotype, as indicated by an increase of the ratio of smooth muscle heavy chain myosin subtypes SM2/SM1. There was, however, no effect on cell growth. High concentrations of antagonist (100 microM) induced apoptosis in about 80% of the treated SMC. This effect was not cell-type-specific and was also seen in skin fibroblasts and immortalized prostate epithelial cells. CONCLUSION: In an easy-to-handle cell culture model of prostatic smooth muscle cells, the effects of alpha1-AR antagonists on cell contraction, growth, and differentiation can be investigated. The results indicate that in addition to inhibition of cell contraction, alpha1-AR antagonists have the potential to induce apoptosis. Copyright 2000 Wiley-Liss, Inc.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056501&dopt=Abstract
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