Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice
Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice
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DOI：
10.1002/ijc.22349
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发表时间：
2007-06-15
影响因子：
6.4
通讯作者：
Keiichi, Takagaki
中科院分区：
文献类型：
--
作者：
Hajime, Morohashi;Shuichi, Yoshihara;Keiichi, Takagaki
我们报道了4-甲基草皮素（ME），一种4-甲基伞形酮衍生物，对胰腺癌细胞合成透明质酸（HA）的抑制作用，以及由此产生的抗癌作用。首先，利用透明质酸结合蛋白（HABP）的竞争抑制分析细胞培养中的HA，研究人胰腺癌细胞系KP1-NK对HA的合成，并利用颗粒排除法观察细胞表面HA，研究细胞外基质HA的合成。我们还分析了ME对细胞粘附和侵袭的抑制作用，这些细胞粘附和侵袭在人胰腺癌的侵袭、生长和转移中发挥作用。此外，我们检测了移植到裸鼠皮下的人胰腺癌细胞中的HA，以研究ME对HA合成的抑制作用。此外，我们还将胰腺癌细胞移植到裸鼠腹部，研究ME是否有可能延长终末期胰腺癌患者的生存期。10 μ M的ME对人胰腺癌细胞的生长没有抑制作用，但对培养细胞的HA合成抑制40%，粘附抑制44%，侵袭抑制40%。ME对裸鼠皮下移植的胰腺癌的皮下肿瘤增殖和HA合成有50%的抑制作用。ME还能延长携带腹腔移植胰腺癌细胞的裸鼠的存活时间。ME通过抑制HA合成抑制胰腺癌的生长和转移。这些结果提示ME可能延长终末期胰腺癌患者的生存时间。(c) 2007 Wiley-Liss, Inc。
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 mu M 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. (c) 2007 Wiley-Liss, Inc.