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Inhibitory effect of 4‐methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice
Author(s) -
Hajime Morohashi,
Shuichi Yoshihara,
Makoto Nakai,
Masanori Yamaguchi,
Ikuko Kakizaki,
Atsushi Kon,
Mutsuo Sasaki,
Keiichi Takagaki
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22349
Subject(s) - pancreatic cancer , metastasis , nude mouse , cancer research , cancer cell , cancer , transplantation , cell culture , in vitro , hyaluronic acid , extracellular matrix , biology , in vivo , pathology , medicine , microbiology and biotechnology , biochemistry , anatomy , genetics
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 μM 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. © 2007 Wiley‐Liss, Inc.