review of literature on clinical pancreatology - The Pancreapedia

expression was not associated with N-cadherin expression, patient outcome, or duration <strong>of</strong>survival. It was concluded that decreased expression <strong>of</strong> nuclear Twist is observed inmalignant pancreatic epithelium. However, use <strong>of</strong> Twist as a diagnostic marker is precludedbecause decreased expression is also seen in chronic pancreatitis. None <strong>of</strong> the markersstudied were predictive <strong>of</strong> patient outcome [376].FibrinogenAlthough changes <strong>of</strong> plasma fibrinogen have been documented in limited pancreaticmalignant tumors, a relationship between plasma fibrinogen and pancreatic cancer in alarge-scale clinical study has not been shown. Therefore, preoperative plasma levels <strong>of</strong>fibrinogen were retrospectively analyzed in 133 pancreatic cancer and 38 pancreatic benigntumor patients. Plasma fibrinogen in pancreatic cancer patients was significantly higher thanthose with benign pancreatic tumor. The percentage <strong>of</strong> hyperfibrinogenemia (>4.20 g/L) inpancreatic cancer was 41 percent, and no positive results were obtained in benignpancreatic disease. Plasma fibrinogen levels were increased in pancreatic cancer withadvanced tumor stage. Accompanied with the progression <strong>of</strong> tumor stage, there was anincrease in the percentage <strong>of</strong> positivity <strong>of</strong> hyperfibrinogenemia in pancreatic cancer. Therewere significantly higher levels <strong>of</strong> plasma fibrinogen in the distant-metastasis group than inthe no-distant-metastasis group. Univariate and multivariate analysis revealed that highplasma fibrinogen levels (>4.20 g/L) were positively associated with distant metastasis <strong>of</strong>pancreatic cancer [377].Glycogen synthas kinase inhibitorRecent studies have demonstrated that glycogen synthase kinase 3beta (GSK-3beta) isoverexpressed in human colon and pancreatic carcinomas, contributing to cancer cellproliferation and survival. Here, we report the design, synthesis, and biological evaluation <strong>of</strong>benz<strong>of</strong>uran-3-yl-(indol-3-yl)maleimides, potent GSK-3beta inhibitors. Some <strong>of</strong> thesecompounds show picomolar inhibitory activity toward GSK-3beta and an enhanced selectivityagainst cyclin-dependent kinase 2 (CDK-2). Selected GSK-3beta inhibitors were tested in thepancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. It was determined that some <strong>of</strong>these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferativeactivity against some or all <strong>of</strong> the pancreatic cancer cells at low micromolar to nanomolarconcentrations. Moreover, it was found that the treatment <strong>of</strong> pancreatic cancer cells withGSK-3beta inhibitors 5 and 26 resulted in suppression <strong>of</strong> GSK-3beta activity and a distinctdecrease <strong>of</strong> the X-linked inhibitor <strong>of</strong> apoptosis (XIAP) expression, leading to significantapoptosis. The present data suggest a possible role for GSK-3beta inhibitors in cancertherapy, in addition to their more prominent applications in CNS disorders [378].Hedgehog pathwayAberrant activation <strong>of</strong> the hedgehog pathway has been observed in multiple human cancers,including pancreatic cancer. For this reason, several small-molecule inhibitors <strong>of</strong> the pathwayhave been advanced to clinical trials to evaluate their efficacy in treating various solidcancers. It has also been suggested that pancreatic cancer is a particularly good candidatefor experimental treatment with hedgehog inhibitors. In the absence <strong>of</strong> ligands, such as sonichedgehog (SHH), the membrane receptor patched (PTCH) blocks the smoothened receptor(SMO), repressing its activity. The binding <strong>of</strong> the SHH ligand to the PTCH receptordiminishes its inhibitory effects on SMO, allowing signal transduction through the pathwaythat culminates in activation and nuclear translocation <strong>of</strong> GLI family zinc finger transcriptionfactors. These transcription factors turn on genes in the nucleus that promote cellularproliferation. Therapeutic blockade <strong>of</strong> the hedgehog pathway eliminates cancer stem cells,improves outcomes, and may effect a cure when combined with gemcitabine in a direct