ABSTRACT
Current management of intraductal papillary mucinous neoplasm (IPMN) according to recently published International Consensus Guidelines depends upon distinguishing it from mucinous cystic neoplasms (MCNs). We have previously shown that prostaglandin E(2) (PGE(2)) is increased in pancreatic cancer tissue over normal controls. Thus, we hypothesized that PGE(2) level in pancreatic fluid differentiates IPMN and MCN and is a biomarker of IPMN dysplasia. Pancreatic fluid was collected in 65 patients at the time of endoscopy (EUS or ERCP) or operation (OR) and analyzed by PGE(2) enzyme-linked immunosorbent assay (ELISA). PGE(2) level was correlated with surgical pathologic diagnosis and dysplastic stage. Mean PGE(2) level (pg/microl) in IPMNs (2.2 +/- 0.6) was greater than in MCNs (0.2 +/- 0.1) (p < 0.05). Mean PGE(2) level of IPMN by dysplastic stage was 0.1 +/- 0.01 (low grade), 1.2 +/- 0.6 (medium grade), 4.4 +/- 0.9 (high grade), and 5.0 +/- 2.3 (invasive). Among invasive IPMN, PGE(2) level dropped in advanced cases with pancreatic ductal obstruction by tumor (0.3 +/- 0) vs non-obstructed (8.6 +/- 2.9). PGE(2) level may help in distinguishing IPMN from MCN in patients with known mucinous lesions. PGE(2) level may also be an indicator of malignant progression of IPMN before ductal obstruction by tumor. Prospective evaluation will be necessary to evaluate the clinical role of PGE(2) level in pancreatic fluid.
Subject(s)
Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Papillary/diagnosis , Carcinoma, Papillary/metabolism , Dinoprostone/metabolism , Pancreatic Cyst/metabolism , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/metabolism , Adenocarcinoma/diagnosis , Adenocarcinoma/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Papillary/pathology , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , HumansABSTRACT
Chemotherapy to date has not been effective in the treatment of human hepatocellular carcinoma. More effective treatment strategies may involve combinations of agents with activity against hepatocellular carcinoma. Parthenolide, a nuclear factor-kappaB (NF-kappaB) inhibitor, and NS398, a cyclooxygenase (COX)-2 inhibitor, have been shown to individually suppress the growth of hepatocellular carcinoma cells in vitro. To investigate their effects in combination, three human hepatocellular carcinoma lines (Hep3B, HepG2, and PLC) were treated with parthenolide and/or NS398. Parthenolide (0.1-10 micromol/L) and NS398 (1-100 micromol/L) each caused concentration-dependent growth inhibition in all cell lines. The addition of parthenolide to NS398 reduced the concentration of NS398 required to inhibit hepatocellular carcinoma growth. Because parthenolide and COX-2 inhibitors have been reported to influence NF-kappaB activity, the effects on this pathway were investigated. The combination of parthenolide/NS398 inhibited phosphorylation of the NF-kappaB-inhibitory protein IkappaBalpha and increased total IkappaBalpha levels. NF-kappaB DNA-binding and transcriptional activities were inhibited more by the combination than the single agents in Hep3B and HepG2 cells but not in PLC cells. The response of PLC cells to NS398 was augmented by p65 small interfering RNA to inhibit NF-kappaB p65 protein expression. The combination of parthenolide/NS398 increased apoptosis only in PLC cells, suggesting that the combination may decrease the apoptotic threshold in these cells. In Hep3B and HepG2 cells, combination treatment with NS398/parthenolide altered the cell cycle distribution resulting in more G0-G1 accumulation. Cyclin D1 levels were further decreased by combination treatment in all cell lines, correlating with the cell cycle alterations. Our results suggest that parthenolide may be effective in combination with COX-2 inhibitors for the treatment of hepatocellular carcinoma.
