Original Article

Digestive Diseases and Sciences

, Volume 54, Issue 2, pp 309-320

Synergistic Growth Inhibitory Effects of the Dual Endothelin-1 Receptor Antagonist Bosentan on Pancreatic Stellate and Cancer Cells

  • Brit FitznerAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock
  • , Peter BrockAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock
  • , Stephanie-Anna HolzhüterAffiliated withInstitute of Pathology, Medical Faculty, University of Rostock
  • , Horst NizzeAffiliated withInstitute of Pathology, Medical Faculty, University of Rostock
  • , Gisela SparmannAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock
  • , Jörg EmmrichAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock
  • , Stefan LiebeAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock
  • , Robert JasterAffiliated withDepartment of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock Email author 

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Abstract

Pancreatic stellate cells (PSC) play a key role in pancreatic fibrosis. Activation of PSC occurs in response to pro-fibrogenic stimuli and is maintained by autocrine loops of mediators, such as endothelin (ET)-1. Here, we have evaluated effects of the dual ET receptor antagonist bosentan in models of pancreatic fibrogenesis and cancer. Cell culture studies revealed that PSC and DSL6A pancreatic cancer cells expressed both ET-1 and ET receptors. Bosentan efficiently inhibited proliferation of both cell types and collagen synthesis in PSC. Expression of the myofibroblastic marker α-smooth muscle actin, connective tissue growth factor, and ET-1 itself in PSC was reduced, while expression of matrix metalloproteinase-9 was enhanced. Like PSC, DSL6A cells secrete less ET-1 when cultured with bosentan. In a rat model of pancreatic fibrosis, chronic pancreatitis induced by dibutyltin dichloride, a tendency towards a diminished disease progression was observed in a subgroup of rats with less severe disease. Together, our results indicate that bosentan exerts antifibrotic and antitumor effects in vitro. Its efficiency in vivo warrants further investigation.

Keywords

Bosentan Fibrosis Pancreatic stellate cells Pancreatic cancer Chronic pancreatitis