Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo.
Prostate
; 69(7): 744-54, 2009 May 15.
Article
em En
| MEDLINE
| ID: mdl-19152342
ABSTRACT
BACKGROUND:
Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors. METHODS ANDRESULTS:
Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent phenotype (i.e., K5, EGFR1, EGF and VEGF-A). Furthermore, nevirapine down-regulated the growth of prostate carcinoma xenografts in athymic mice and induced a differentiated phenotype in vivo with increased K18 expression. Interestingly, the drug restored androgen signaling by enhancing the ability of tumor cells to respond to dihydrotestosterone stimulation and to the antiproliferative activity of the androgen receptor blocker bicalutamide. Finally, nevirapine pretreatment increased the susceptibility of tumor cells to docetaxel, by enhancing their ability to undergo apoptosis.CONCLUSIONS:
These data suggest that nevirapine may be clinically tested in human hormone-refractory prostate carcinoma to restore the susceptibility to androgen deprivation therapy or to docetaxel.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Receptores Androgênicos
/
Inibidores da Transcriptase Reversa
/
Nevirapina
/
Neoplasias Hormônio-Dependentes
Tipo de estudo:
Clinical_trials
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Prostate
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Itália