title: Antitumor effects of the hyaluronan inhibitor 4-methylumbelliferone on pancreatic cancer.
abstract: Hyaluronan (HA) is a major component of the extracellular matrix (ECM), and influences tumor invasion and metastasis. In a previous study, the present authors reported for the first time that 4-methylumbelliferone (MU) inhibited HA synthesis and suppressed tumor growth. However, the localization of HA and the changes in ECM morphology caused by MU in pancreatic cancer remain to be examined in detail. In the present study, the cytotoxicity of MU and its effect on cellular proliferation was evaluated in the human pancreatic cancer cell line MIA PaCa-2. The amount of HA synthesized and the retention of HA around the cells were quantitatively and immunohistochemically analyzedin vitroandin vivo. Structural changes in the ECM in the tumor tissue were investigated using an electron microscope. MU treatment led to a decrease in extracellular HA retention, as evidenced by a particle exclusion assay and immunohistochemical staining. Cell proliferation was suppressed by MU in a dose-dependent manner. The release of lactate dehydrogenase into the culture medium due to damage to the cellular membrane did not increase following MU administration. In tumor-inoculated mice, MU suppressed any increase in tumor volume and decreased the quantity of HA. Electron microscopy revealed that MU attenuated the intercellular space and caused it to be less cohesive. These data indicate that MU inhibits HA synthesis and reduces the amount of HA in the ECM while exhibiting no obvious cytotoxic effect. These findings suggest that MU has potential as a novel therapeutic agent for pancreatic cancer.
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kudo
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Anatomical Science, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimoda
authors.affiliation: Department of Glycobiomedicine, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan; Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Suto
authors.affiliation: Department of Glycobiomedicine, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan; Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Negishi
authors.affiliation: Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kakizaki
authors.affiliation: Department of Glycobiomedicine, Center for Advanced Medical Research, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hakamada
keywords: 4-methylumbelliferone; chemosensitizer; extracellular matrix; hyaluronan; pancreatic cancer