title: Mechanisms of synergism between antagonists of growth hormone-releasing hormone and antagonists of luteinizing hormone-releasing hormone in shrinking experimental benign prostatic hyperplasia.
abstract: BACKGROUND
  Benign prostatic hyperplasia (BPH) affects aging men. Combined therapy with antagonists of growth hormone-releasing hormone (GHRH) and of luteinizing hormone-releasing hormone (LHRH or GnRH) induces prostate shrinkage in rat models. We investigated the mechanisms of action of this combination on cell cycle traverse and expression of prostatic genes.
  
  
  METHODS
  Effects of GHRH antagonist, JMR-132 (40 µg/day), the LHRH antagonist, cetrorelix (0.625 mg/kg), and their combination were evaluated on testosterone-induced benign prostatic hyperplasia in male Wistar rats. Influence of JMR-132, cetrorelix, and their combinations on cell viability was assessed by MTS assay in BPH-1 human prostate epithelial cells and WPMY-1 normal prostate stromal cells. Cell cycle was analyzed by laser flow cytometry. Real-time PCR arrays were performed.
  
  
  RESULTS
  The combination of antagonists caused marked shrinkage of rat prostate (29.5%). In vitro, JMR-132 plus cetrorelix (both 5µM) produced synergistic (57.4%) inhibition of growth of BPH-1 cells, but a lesser inhibition (46%) of WPMY-1 cells. Co-treatment of with JMR-132 plus cetrorelix induced a significant increase of BPH-1 cells blocked in S-phase plus cells with lower G0 /G1 and G2 /M DNA content. Significant changes in expression of >40 gene transcripts related to growth factors, inflammatory cytokines, and signal transduction were identified.
  
  
  CONCLUSIONS
  GHRH antagonist and LHRH antagonist combination potentiates rat prostate weight reduction and synergistically inhibits of growth of BPH-1 leading to cell cycle arrest in S-phase. These effects were lesser in normal stromal prostate cell line, WPMY-1. Our findings suggest that GHRH antagonists could be useful for BPH therapy, possibly in combination with LHRH antagonists.
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida 33125, USA. ferencrick@gmail.com
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Andrew
authors.initials: A
authors.lastname: Abi-Chaker
authors.forename: Awtar
authors.initials: A
authors.lastname: Krishan
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009929:Organ Size; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C534070:GHRH(1-29)NH2, PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-; D007987:Gonadotropin-Releasing Hormone; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; C062876:cetrorelix