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Titre du document / Document title

Suppression of human prostate cancer cell growth by α1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis

Auteur(s) / Author(s)

KYPRIANOU N. (1) ; BENNING C. M. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Division of Urology, Department of Biochemistry and Molecular Biology, and University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, ETATS-UNIS

Résumé / Abstract

Recent evidence from our laboratory has demonstrated that α1-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 al-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three al-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 phenoxy-benzamine, an irreversible inhibitor of al-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 al-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.

Revue / Journal Title

Cancer research    ISSN  0008-5472   CODEN CNREA8 

Source / Source

2000, vol. 60, no16, pp. 4550-4555 (30 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Association for Cancer Research, Philadelphia, PA, ETATS-UNIS  (1941) (Revue)

Mots-clés anglais / English Keywords

Treatment

;

Antineoplastic agent

;

Treatment efficiency

;

Human

;

In vitro

;

Established cell line

;

Malignant tumor

;

Prostate

;

Biological activity

;

α1-Adrenergic receptor

;

Antagonist

;

Doxazosin

;

Terazosin

;

Mechanism of action

;

Cell death

;

Apoptosis

;

Animal

;

Mouse

;

Animal model

;

Cell proliferation

;

In vivo

;

Rodentia

;

Mammalia

;

Vertebrata

;

Male genital diseases

;

Urinary system disease

;

Prostate disease

;

Mots-clés français / French Keywords

Traitement

;

Anticancéreux

;

Efficacité traitement

;

Homme

;

In vitro

;

Lignée cellulaire établie

;

Tumeur maligne

;

Prostate

;

Activité biologique

;

Récepteur α1-adrénergique

;

Antagoniste

;

Doxazosine

;

Térazosine

;

Mécanisme action

;

Mort cellulaire

;

Apoptose

;

Animal

;

Souris

;

Modèle animal

;

Multiplication cellulaire

;

In vivo

;

Rodentia

;

Mammalia

;

Vertebrata

;

Appareil génital mâle pathologie

;

Appareil urinaire pathologie

;

Prostate pathologie

;

Mots-clés espagnols / Spanish Keywords

Tratamiento

;

Anticanceroso

;

Eficacia tratamiento

;

Hombre

;

In vitro

;

Línea celular establecida

;

Tumor maligno

;

Prostata

;

Actividad biológica

;

Receptor α1-adrenérgico

;

Antagonista

;

Doxazosina

;

Terazosina

;

Mecanismo acción

;

Muerte celular

;

Apoptosis

;

Animal

;

Ratón

;

Modelo animal

;

Multiplicación celular

;

In vivo

;

Rodentia

;

Mammalia

;

Vertebrata

;

Aparato genital macho patología

;

Aparato urinario patología

;

Prostata patología

;

Localisation / Location

INIST-CNRS, Cote INIST : 5088, 35400009125684.0420

Nº notice refdoc (ud4) : 1495864



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