title: Potential therapeutic applications of phosphodiesterase inhibition in prostate cancer.
abstract: OBJECTIVE
  Phosphodiesterases (PDEs) play a role in controlling cyclic nucleotide action, including cyclic guanosine monophosphate (cGMP). Previous studies have ascribed a protective role of cGMP signaling on hypoxia-mediated cancer progression. Herein, we determine their potential role in hypoxia-mediated chemoresistance and immune escape.
  
  
  METHODS
  Phosphodiesterase assays were used to measure PDE activity in prostate cancer cell lines (DU145, PC3). Immunoblots were performed to determine the presence of PDEs in human prostate tissue samples. The effect of PDE inhibition on hypoxia-induced chemoresistance (compared to normoxic controls, 20% O2) was determined using clonogenic assays. Flow cytometry was used to determine the effects of PDE inhibition on surface MHC class I-related chain A (MICA), a natural killer (NK) cell-activating ligand. A mouse model was used to evaluate the in vivo effects of PDE inhibition on the growth of human prostate cancer cells.
  
  
  RESULTS
  PDE5 and PDE11 were the most prominent PDEs in the cell lines, representing between 86 and 95% of the total cGMP-specific PDE activity. Treatment of DU-145 cells with a PDE inhibitor significantly reduced the hypoxia-associated acquisition of resistance to doxorubicin, with a mean 51% reduction in surviving fraction compared to controls (p < 0.001, ANOVA). As well, PDE inhibition completely reversed (p = 0.02, ANOVA) hypoxia-induced shedding of the immune stimulatory molecule, MICA, and attenuated the growth of human prostate tumor xenografts in an NK cell-competent murine model (p = 0.03, Wilcoxon, Mann-Whitney).
  
  
  CONCLUSIONS
  These results suggest a rationale for future studies on the potential therapeutic applications of PDE inhibitors in men with prostate cancer.
authors.affiliation: Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hamilton
authors.forename: Nianping
authors.initials: N
authors.lastname: Hu
authors.forename: Klodiana
authors.initials: K
authors.lastname: Kolomitro
authors.forename: Erin N
authors.initials: EN
authors.lastname: Bell
authors.forename: Donald H
authors.initials: DH
authors.lastname: Maurice
authors.forename: Charles H
authors.initials: CH
authors.lastname: Graham
authors.forename: D Robert
authors.initials: DR
authors.lastname: Siemens
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D057075:Enzyme Assays; D015395:Histocompatibility Antigens Class I / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D010726:Phosphodiesterase Inhibitors; D004317:Doxorubicin; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517275:PDE2A protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C406737:PDE11A protein, human