Antiproliferative effects of CC-8062 and CC-8075 in pancreatic cancer cells.
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.
Mouratidis
Petros X E
PX
Division of Oncology, Department of Cellular and Molecular Medicine, St George's University of London, London, UK. pmouratidis@hotmail.com
Colston
Kay W
KW
Bartlett
Jake Blake
JB
Muller
George W
GW
Man
Hon-Wah
HW
Stirling
David
D
Dalgleish
Angus G
AG
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
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