title: Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864.
abstract: OBJECTIVE
  Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells.
  
  
  METHODS
  Experiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23766 and EHT1864) on contractility were assessed in the organ bath. The effects of Rac inhibitors were assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining and cell growth using an 5-ethynyl-2'-deoxyuridine assay.
  
  
  RESULTS
  Expression of Rac1-3 was observed in prostate samples from each patient. Immunoreactivity for Rac1-3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine or electrical field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64 and 81% after incubation with NSC23766 (50 or 100 μM) or EHT1864 (25 μM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal disorganization in WPMY-1 cells. Both inhibitors impaired the growth of WPMY-1 cells.
  
  
  CONCLUSIONS
  Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.|Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors: Y
authors: Y
authors: Wang
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.|University Hospital for Urology and Andrology, Salzburg, Austria.
authors: T
authors: T
authors: Kunit
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: A
authors: A
authors: Ciotkowska
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: B
authors: B
authors: Rutz
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: A
authors: A
authors: Schreiber
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: F
authors: F
authors: Strittmatter
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: R
authors: R
authors: Waidelich
authors: Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors: C
authors: C
authors: Liu
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: C G
authors: CG
authors: Stief
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: C
authors: C
authors: Gratzke
authors: Department of Urology, Ludwig Maximilian University, Munich, Germany.
authors: M
authors: M
authors: Hennenberg
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011467:Prostate / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000634:Aminoquinolines; D011743:Pyrimidines; D011753:Pyrones; D011804:Quinolines; D012333:RNA, Messenger; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C506907:EHT 1864; C487513:NSC 23766; C107953:RAC1 protein, human; C411563:RAC3 protein, human
references: Br J Pharmacol. 2013 Dec;170(8):1797-867
references: 24528243
references: J Cell Mol Med. 2011 Jul;15(7):1551-63
references: 20716113
references: Neurourol Urodyn. 2007 Oct;26(6 Suppl):948-54
references: 17696159
references: Cardiovasc Res. 2010 Apr 1;86(1):131-40
references: 19969623
references: Curr Biol. 2010 Nov 9;20(21):1881-9
references: 20951045
references: J Cell Biol. 1997 Aug 25;138(4):913-26
references: 9265656
references: Proc Natl Acad Sci U S A. 2004 May 18;101(20):7618-23
references: 15128949
references: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references: 24234439
references: Invest Ophthalmol Vis Sci. 2012 Jul;53(8):4682-91
references: 22695959
references: Urology. 2012 Mar;79(3):745.e5-12
references: 22197205
references: Cytokine. 2013 Oct;64(1):251-7
references: 23876400
references: PLoS One. 2014;9(3):e92398
references: 24667766
references: J Biol Chem. 2007 Dec 7;282(49):35666-78
references: 17932039
references: J Cell Physiol. 2005 Aug;204(2):412-22
references: 15706595
references: J Biol Chem. 2005 Nov 11;280(45):37516-25
references: 16150730
references: Indian J Urol. 2014 Apr;30(2):181-8
references: 24744518
references: Atherosclerosis. 2008 Jan;196(1):92-7
references: 17350025
references: Curr Opin Pharmacol. 2010 Apr;10(2):116-21
references: 20060361
references: Am J Physiol Heart Circ Physiol. 2013 Jan 15;304(2):H294-302
references: 23161879
references: Neurourol Urodyn. 2014 Sep;33(7):1074-85
references: 24038148
references: J Cardiovasc Pharmacol. 2013 Jun;61(6):536-44
references: 23429587
references: PLoS One. 2013;8(9):e74924
references: 24040362
references: Ann Pharmacother. 2014 Mar;48(3):343-8
references: 24311727
references: Am J Physiol Lung Cell Mol Physiol. 2008 Apr;294(4):L698-704
references: 18310224
references: Oncogene. 2009 Apr 23;28(16):1853-63
references: 19305425
references: Am J Physiol Renal Physiol. 2014 Oct 1;307(7):F823-32
references: 25056351
references: Cell Commun Signal. 2013;11:80
references: 24144209
references: Nat Rev Urol. 2013 Jan;10(1):49-54
references: 23165396
references: J Physiol. 2014 Mar 1;592(5):915-26
references: 24297853
references: Mol Med Rep. 2012 Feb;5(2):313-6
references: 22038307
references: Nephron Exp Nephrol. 2014;126(1):16-24
references: 24603367
references: J Am Soc Nephrol. 2012 Jun;23(6):997-1007
references: 22440899
references: Exp Cell Res. 2012 Nov 1;318(18):2269-83
references: 22796473
references: Br J Pharmacol. 2006 Feb;147 Suppl 2:S88-119
references: 16465187
references: J Urol. 2009 May;181(5):2214-21; discussion 2221-2
references: 19296986
references: Prostate. 1997 Feb 15;30(3):202-15
references: 9122046
references: Br J Pharmacol. 2013 Dec;170(8):1459-581
references: 24517644
references: PLoS One. 2013;8(8):e71080
references: 23951087
references: J Cell Sci. 2004 Mar 15;117(Pt 8):1301-12
references: 15020670
references: Lab Invest. 2014 Sep;94(9):1054-63
references: 25046439
references: J Mol Cell Cardiol. 2012 Aug;53(2):165-75
references: 22564263
references: Cardiovasc Res. 2013 Jun 1;98(3):428-36
references: 23417038
references: Physiol Rev. 2001 Jan;81(1):153-208
references: 11152757
references: Neuropharmacology. 2014 Oct;85:508-16
references: 24953831
references: Eur Urol. 2009 Apr;55(4):864-73
references: 19027219
references: Blood. 2002 Dec 15;100(13):4462-9
references: 12453877
references: Handb Exp Pharmacol. 2011;(202):117-48
references: 21290225
references: Curr Urol Rep. 2007 Jul;8(4):269-74
references: 18519010
references: J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46
references: 19934221
references: BJU Int. 2002 Feb;89(3):214-25
references: 11856101
references: Methods Enzymol. 2006;406:554-65
references: 16472687
references: Int J Urol. 2012 Sep;19(9):867-74
references: 22574733
references: PLoS One. 2012;7(7):e40594
references: 22808202
references: Eur Urol. 2013 Jul;64(1):118-40
references: 23541338
references: J Cardiovasc Pharmacol. 2011 Jun;57(6):656-65
references: 21386710