title: Phosphodiesterase 4D inhibitors limit prostate cancer growth potential.
abstract: Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is overexpressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacologic inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), androgen receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the SHH pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from cocultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared with vehicle-treated controls. These studies suggest the pharmacologic inhibition of PDE4D using small-molecule inhibitors is an effective option for prostate cancer therapy.
  
  
  CONCLUSIONS
  PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Ginny L
authors.initials: GL
authors.lastname: Powers
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Kimberly D P
authors.initials: KD
authors.lastname: Hammer
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, Wisconsin. Department of Chemical Engineering, University of Puerto Rico, Mayaguez, Puerto Rico.
authors.forename: Maribella
authors.initials: M
authors.lastname: Domenech
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Katsiaryna
authors.initials: K
authors.lastname: Frantskevich
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Malinowski
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Wade
authors.initials: W
authors.lastname: Bushman
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: David J
authors.initials: DJ
authors.lastname: Beebe
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin. marker@wisc.edu.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Marker
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage; D053823:Hedgehog Proteins / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis; D009287:Naphthyridines / Q000008:administration & dosage; D009570:Nitriles / Q000008:administration & dosage; D010069:Oxadiazoles / Q000008:administration & dosage; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011944:Receptors, Androgen / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D003509:Cyclohexanecarboxylic Acids; D053823:Hedgehog Proteins; C451724:NVP ABE171; D009287:Naphthyridines; D009570:Nitriles; D010069:Oxadiazoles; D058988:Phosphodiesterase 4 Inhibitors; D011944:Receptors, Androgen; C509239:SHH protein, human; C433247:Cilomilast; D020929:Mitogen-Activated Protein Kinase Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4