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

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 o...

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Bibliographic Details
Published in:Digestive diseases and sciences 2009-02, Vol.54 (2), p.309-320
Main Authors: Fitzner, Brit, Brock, Peter, Holzhüter, Stephanie-Anna, Nizze, Horst, Sparmann, Gisela, Emmrich, Jörg, Liebe, Stefan, Jaster, Robert
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological and medical sciences
Carcinoma - drug therapy
Cell Line, Tumor
Coculture Techniques
Collagen - metabolism
Endothelin Receptor Antagonists
Endothelin-1 - metabolism
Feeding. Feeding behavior
Fibrosis - chemically induced
Fibrosis - drug therapy
Fundamental and applied biological sciences. Psychology
Gastroenterology
Gastroenterology. Liver. Pancreas. Abdomen
Hepatology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Medicine
Medicine & Public Health
Oncology
Organotin Compounds - toxicity
Original Article
Other diseases. Semiology
Pancreas - drug effects
Pancreas - metabolism
Pancreas - pathology
Pancreatic Neoplasms - drug therapy
Pancreatitis, Chronic - chemically induced
Pancreatitis, Chronic - drug therapy
Rats
Receptors, Endothelin - metabolism
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
Transplant Surgery
Tumors
Vertebrates: anatomy and physiology, studies on body, several organs or systems
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Summary: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.
ISSN:0163-2116
1573-2568
DOI:10.1007/s10620-008-0366-z