Mechanisms of inhibition of human benign prostatic hyperplasia in vitro by the luteinizing hormone-releasing hormone antagonist cetrorelix.
OBJECTIVE
To assess the mechanism by which the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix exerts its effects in men with benign prostatic hyperplasia (BPH), as it produces a long-lasting improvement in lower urinary tract symptoms that is only partly accounted for by the transient reduction in testosterone levels, and the beneficial results could be due to direct inhibitory effects of cetrorelix on the prostate exerted through prostatic LHRH receptors.


METHODS
Using the BPH-1 cell line we evaluated the effects of cetrorelix in vitro on the proliferation and the expression of receptors for LHRH, epidermal growth factor (EGF), α(1A) -adrenergic receptor, STAT-3 transcription factor and the response to growth factors insulin-like growth factor (IGF)-1 and -II and fibroblast growth factor (FGF)-2.


RESULTS
There was expression of LHRH receptors in the human BPH-1 cell line. Cetrorelix had inhibitory effects on the proliferation rate of BPH-1 cells, also reflected by the decrease in the expression of the proliferating cell nuclear antigen (PCNA). Cetrorelix inhibited the stimulatory effect of the growth factors IGF-I and -II and FGF-2 on the proliferation of this line. Cetrorelix also downregulated the expression of the receptors for LHRH and EGF, as well as of α(1A) -adrenergic receptors, and inhibited the activation of the STAT3 transcription factor.


CONCLUSIONS
The results show that in vitro cetrorelix can directly inhibit the proliferation rate of the human BPH-1 cell line by counteracting growth factors like IGF-I and -II and FGF-2, and downregulating the LHRH receptor and α-adrenergic receptors, as well as transcription factors.
Siejka
Agnieszka
A
Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, USA.
Schally
Andrew V
AV
Block
Norman L
NL
Barabutis
Nektarios
N
D000704:Analysis of Variance; D015153:Blotting, Western; D002460:Cell Line; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000150:complications / Q000188:drug therapy*; D053448:Prostatism / Q000188:drug therapy* / Q000209:etiology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D006727:Hormone Antagonists; D018969:Insulin-Like Growth Factor Binding Proteins; D010446:Peptide Fragments; D011942:Receptors, Adrenergic, alpha; D011966:Receptors, LHRH; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D005346:Fibroblast Growth Factors; C052888:fibroblast growth factor (1-10); D066246:ErbB Receptors; C062876:cetrorelix