Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist.
Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA. ferencrick@gmail.com
Ferenc G
FG
Rick
Andrew
A
Abi-Chaker
Luca
L
Szalontay
Roberto
R
Perez
Miklos
M
Jaszberenyi
Arumugam R
AR
Jayakumar
Nagarajarao
N
Shamaladevi
Karoly
K
Szepeshazi
Irving
I
Vidaurre
Gabor
G
Halmos
Awtar
A
Krishan
Norman L
NL
Block
Andrew V
AV
Schally
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001839:Bombesin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood; D011467:Prostate / Q000166:cytology* / Q000187:drug effects; D011470:Prostatic Hyperplasia / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000633:toxicity; D013778:Tetrazolium Salts; D013844:Thiazoles
D016328:NF-kappa B; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D011944:Receptors, Androgen; D013778:Tetrazolium Salts; D013844:Thiazoles; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; D013739:Testosterone; D019886:Gastrin-Releasing Peptide; D051546:Cyclooxygenase 2; C022616:thiazolyl blue; D001839:Bombesin