title: The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice.
abstract: There is accumulating evidence that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, promote the progression of pancreatic cancer. The interactions between PSCs and pancreatic cancer have attracted substantial attention as a novel therapeutic target for the treatment of pancreatic cancer. We examined here the effects of olmesartan, an angiotensin II type I receptor blocker, on pancreatic cancer-associated fibrosis using a subcutaneous tumor model developed by co-injection of pancreatic cancer cells with PSCs in nude mice. Co-injection of pancreatic cancer cells AsPC-1 with PSCs increased the size of tumors compared with AsPC-1 cells alone. Olmesartan administrated at 10 mg/kg in drinking water inhibited the growth of subcutaneous tumors derived from the co-injection, but not those derived from mono-injection. This effect was accompanied by decreased expression of α-smooth muscle actin (a marker of activated PSCs) and collagen deposition. The inhibitory effect of olmesartan was also observed even if it was administrated after significant development of subcutaneous tumors. In addition, olmesartan decreased cell growth and type I collagen production in PSCs in vitro. These results suggest that olmesartan inhibited the growth of tumors by targeting stellate cell activities, and that olmesartan might be useful as an anti-fibrosis therapy in pancreatic cancer.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. amasamune@med.tohoku.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takikawa
authors.forename: Shin
authors.initials: S
authors.lastname: Miura
authors.forename: Eriko
authors.initials: E
authors.lastname: Nakano
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000199:Actins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000068557:Olmesartan Medoxomil; D010190:Pancreatic Neoplasms / Q000503:physiopathology / Q000517:prevention & control*; D058954:Pancreatic Stellate Cells / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D024042:Collagen Type I; D007093:Imidazoles; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil