title: Antiproliferative effects of CC-8062 and CC-8075 in pancreatic cancer cells.
abstract: OBJECTIVE
  Pancreatic cancer is one of the leading causes of cancer related deaths in the western world. It is also resistant to most chemotherapeutic modalities. Phosphodiesterase-4 inhibitors (PDE4is) have found applications in the treatment of respiratory diseases. The aim of this study is to investigate the cytotoxic effect of 2 novel PDE4is, the CC-8075 and CC-8062 compounds in pancreatic cancer cells.
  
  
  METHODS
  Cell proliferation was measured using the sulforhodamine B protein dye. Induction of apoptosis was detected using enzyme-linked immunosorbent assay. Regulation of proteins and posttranslational modifications were determined using immunoblotting.
  
  
  RESULTS
  Treatment of pancreatic cancer cells with CC-8075 and CC-8062 reduces their proliferation and increases apoptosis that is caspase dependent in T3M4 cells. Furthermore, PDE4is increase phosphorylation of p38MAPK, mitogen-activated protein kinase (MAPK) kinase 3/6,MAPKYactivated protein kinase 2, Atf2, and Hsp27. The use of thep38MAPK-specific inhibitors SB202190 and SB203580 results in a modest reduction in PDE4i-induced apoptosis in T3M4 cells. Also, retinoids enhance apoptosis induced by CC-8075 and CC-8062 in GER cells.
  
  
  CONCLUSIONS
  These results highlight the antiproliferative effects of the phosphodiesterase inhibitors CC-8075 and CC-8062 in pancreatic cancer cells and suggest that activation of p38MAPK signaling pathway may be associated with this process.
authors.affiliation: Division of Oncology, Department of Cellular and Molecular Medicine, St George's University of London, London, UK. pmouratidis@hotmail.com
authors.forename: Petros X E
authors.initials: PX
authors.lastname: Mouratidis
authors.forename: Kay W
authors.initials: KW
authors.lastname: Colston
authors.forename: Jake Blake
authors.initials: JB
authors.lastname: Bartlett
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.forename: David
authors.initials: D
authors.lastname: Stirling
authors.forename: Angus G
authors.initials: AG
authors.lastname: Dalgleish
mesh_terms: D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077556:Alitretinoin; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole