title: Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice.
abstract: We report the inhibitory effect of 4-methylesculetin (ME), a 4-methylumbelliferone derivative, on hyaluronan (HA) synthesis by pancreatic cancer cells, and its resulting anticancer action. First, HA in cell culture was analyzed using competitive inhibition with hyaluronic acid-binding protein (HABP) to study HA synthesis by the human pancreatic cancer cell line KP1-NK, and cell-surface HA was visualized using a particle-exclusion assay to study the synthesis of extracellular matrix HA. We also analyzed the inhibitory effect of ME on cell adhesion and invasion, which play a role in the invasion, growth and metastasis of human pancreatic cancer. Furthermore, we examined HA in human pancreatic cancer cells transplanted into the hypodermis of nude mice to study the inhibitory effect of ME on HA synthesis. Moreover, pancreatic cancer cells were also transplanted into the abdomen of nude mice to study whether ME would have the potential to prolong the survival of patients with end-stage pancreatic cancer. ME at 10 muM did not inhibit the growth of human pancreatic cancer cells, but inhibited HA synthesis in cell culture by 40%, adhesion by 44% and invasion by 40%. ME inhibited the proliferation of subcutaneous tumors and HA synthesis (by 50%) of pancreatic cancer transplanted into the hypodermis of nude mice. ME also prolonged the survival time of nude mice bearing abdominally transplanted pancreatic cancer cells. ME inhibited pancreatic cancer growth and metastasis by inhibition of HA synthesis. These results suggest that ME may prolong the survival time of patients with end-stage pancreatic cancer.
authors.affiliation: Department of Surgery, Hirosaki University School of medicine, Hirosaki, Japan.
authors.forename: Morohashi
authors.initials: M
authors.lastname: Hajime
authors.forename: Yoshihara
authors.initials: Y
authors.lastname: Shuichi
authors.forename: Nakai
authors.initials: N
authors.lastname: Makoto
authors.forename: Yamaguchi
authors.initials: Y
authors.lastname: Masanori
authors.forename: Kakizaki
authors.initials: K
authors.lastname: Ikuko
authors.forename: Kon
authors.initials: K
authors.lastname: Atsushi
authors.forename: Sasaki
authors.initials: S
authors.lastname: Mutsuo
authors.forename: Takagaki
authors.initials: T
authors.lastname: Keiichi
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012603:Scopoletin / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D006820:Hyaluronic Acid; D012603:Scopoletin