Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.

The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S)-11 and (R)-...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Anna Tesei, Carlo Leonetti, Marzia Di Donato, Elisa Gabucci, Manuela Porru, Greta Varchi, Andrea Guerrini, Dino Amadori, Chiara Arienti, Sara Pignatta, Giulia Paganelli, Michele Caraglia, Gabriella Castoria, Wainer Zoli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1862085ca7bf4eeca8183e3e7658b889
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1862085ca7bf4eeca8183e3e7658b889
record_format	dspace
spelling	oai:doaj.org-article:1862085ca7bf4eeca8183e3e7658b8892021-11-18T07:46:21ZEffect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.1932-620310.1371/journal.pone.0062657https://doaj.org/article/1862085ca7bf4eeca8183e3e7658b8892013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23667504/?tool=EBIhttps://doaj.org/toc/1932-6203The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S)-11 and (R)-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC). In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R)-9 and (S)-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R)-bicalutamide), also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R)-9 was higher than that of (S)-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S)-11 and (R)-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R)-9 did not reveal the presence of adverse events. Furthermore, (R)-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R)-9 and (S)-11, making them a potentially attractive option for the treatment of CRPC.Anna TeseiCarlo LeonettiMarzia Di DonatoElisa GabucciManuela PorruGreta VarchiAndrea GuerriniDino AmadoriChiara ArientiSara PignattaGiulia PaganelliMichele CaragliaGabriella CastoriaWainer ZoliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e62657 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Tesei Carlo Leonetti Marzia Di Donato Elisa Gabucci Manuela Porru Greta Varchi Andrea Guerrini Dino Amadori Chiara Arienti Sara Pignatta Giulia Paganelli Michele Caraglia Gabriella Castoria Wainer Zoli Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
description	The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S)-11 and (R)-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC). In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R)-9 and (S)-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R)-bicalutamide), also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R)-9 was higher than that of (S)-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S)-11 and (R)-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R)-9 did not reveal the presence of adverse events. Furthermore, (R)-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R)-9 and (S)-11, making them a potentially attractive option for the treatment of CRPC.
format	article
author	Anna Tesei Carlo Leonetti Marzia Di Donato Elisa Gabucci Manuela Porru Greta Varchi Andrea Guerrini Dino Amadori Chiara Arienti Sara Pignatta Giulia Paganelli Michele Caraglia Gabriella Castoria Wainer Zoli
author_facet	Anna Tesei Carlo Leonetti Marzia Di Donato Elisa Gabucci Manuela Porru Greta Varchi Andrea Guerrini Dino Amadori Chiara Arienti Sara Pignatta Giulia Paganelli Michele Caraglia Gabriella Castoria Wainer Zoli
author_sort	Anna Tesei
title	Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
title_short	Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
title_full	Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
title_fullStr	Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
title_full_unstemmed	Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.
title_sort	effect of small molecules modulating androgen receptor (sarms) in human prostate cancer models.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/1862085ca7bf4eeca8183e3e7658b889
work_keys_str_mv	AT annatesei effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT carloleonetti effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT marziadidonato effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT elisagabucci effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT manuelaporru effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT gretavarchi effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT andreaguerrini effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT dinoamadori effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT chiaraarienti effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT sarapignatta effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT giuliapaganelli effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT michelecaraglia effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT gabriellacastoria effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels AT wainerzoli effectofsmallmoleculesmodulatingandrogenreceptorsarmsinhumanprostatecancermodels
_version_	1718422956309217280

Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models.

Ejemplares similares