Acenocoumarol increases the severity of cerulein-induced acute pancreatitis in rats

Abstract

s / Pancreatology 12 (2012) 502–597 509 Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Early diagnosis is rare and treatment options are limited. The Notch pathway has recently emerged as a candidate drug target. Notch signalling is important in PDAC initiation and maintenance. This provides a rationale for further analysis of Notch signalling in PDAC carcinogenesis Aims: Based on the known roles of Notch in development and stem cell biology, we investigated the effects of GSI IX on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. Methods: We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. In addition, sorted CD44+/EpCAM+ cells were subcutaneously injected into the nude mice (NMRI-nu/nu) and treated with vehicle or with GSI IX. The effect of GSI on Xenograft tumors, EMT markers, and cell proliferation was evaluated. Results: GSI IX inhibited pancreatic cancer cell proliferation, migration and invasion in a dose-dependent manner. Apoptosis was induced after GSI IX treatment and EMT markers reversed partially. GSI IX significantly inhibited the growth of pancreatic tumor initiating CD44+/EpCAM+ cells in vitro and in a xenograft mouse model. Conclusion: Our data support the central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.