title: P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate.
abstract: Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients' adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1-10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.|Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gratzke
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tamalunas
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wiemer
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Ciotkowska
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Rutz
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Waidelich
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Strittmatter
authors.affiliation: Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Stief
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hennenberg
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004220:Disulfides / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C581573:6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)pyrido(2,3-d)pyrimidin-7(8H)-one; D058668:Adrenergic alpha-1 Receptor Antagonists; D004220:Disulfides; D019332:Endothelin-1; C541795:IPA-3 compound; D009284:Naphthols; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D054462:p21-Activated Kinases; D009638:Norepinephrine