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 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 alpha-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.
Fitzner
Brit
B
Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E.-Heydemann-Str. 6, 18057, Rostock, Germany.
Brock
Peter
P
Holzhüter
Stephanie-Anna
SA
Nizze
Horst
H
Sparmann
Gisela
G
Emmrich
Jörg
J
Liebe
Stefan
S
Jaster
Robert
R
D000818:Animals; D000077300:Bosentan; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy; D009947:Organotin Compounds / Q000633:toxicity; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009947:Organotin Compounds; D017466:Receptors, Endothelin; D013449:Sulfonamides; D003094:Collagen; C020735:dibutyldichlorotin; D000077300:Bosentan