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

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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.

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Acknowledgments

We gratefully acknowledge the excellent technical assistance of Mrs. Katja Bergmann, Mrs. Helga Schulze, and Mrs. Katrin Sievert-Küchenmeister. The in vitro studies with PSC and the in vivo studies with DBTC-treated rats were supported by a grant from the Deutsche Forschungsgemeinschaft. Investigations regarding bosentan effects in pancreatic cancer cells were funded by Actelion.

Competing Interests

The following relationship could be construed as resulting in an actual, potential, or apparent conflict of interest with regard to the manuscript: The laboratory of R. Jaster has received research support from Actelion for the studies with DSL6A pancreatic cancer cells.

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E.-Heydemann-Str. 6, 18057, Rostock, Germany

    Brit Fitzner, Peter Brock, Gisela Sparmann, Jörg Emmrich, Stefan Liebe & Robert Jaster

  2. Institute of Pathology, Medical Faculty, University of Rostock, Strempelstr. 14, 18057, Rostock, Germany

    Stephanie-Anna Holzhüter & Horst Nizze

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  1. Brit Fitzner
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  2. Peter Brock
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Correspondence to Robert Jaster.

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Fitzner, B., Brock, P., Holzhüter, SA. et al. Synergistic Growth Inhibitory Effects of the Dual Endothelin-1 Receptor Antagonist Bosentan on Pancreatic Stellate and Cancer Cells. Dig Dis Sci 54, 309–320 (2009). https://doi.org/10.1007/s10620-008-0366-z

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