A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for scirrhous gastric cancer
A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for scirrhous gastric cancer
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DOI：
10.1053/j.gastro.2006.08.030
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发表时间：
2006-11-01
期刊：
影响因子：
29.4
通讯作者：
Hirakawa, Kosei
中科院分区：
文献类型：
--
作者：
Nakamura, Kazunori;Yashiro, Masakazu;Hirakawa, Kosei
背景与目的：在所有胃癌中，硬化性胃癌的死亡率最高。据报道，预后不良与K-Samii基因扩增有关，K-Samii基因编码成纤维细胞生长因子受体2型(FGFR-2)。Ki23057是一种新开发的小分子作用K-SamII/FGF-R-2自磷酸化抑制剂，是一种与三磷酸腺苷竞争结合部位的酪氨酸激酶抑制剂。本研究的目的是阐明Ki23057分子靶向治疗硬化性胃癌的可能性。方法：选用5株人胃癌细胞株。OCUM-2MD3和OCUM-8来源于硬癌。MKN-7、MKN-4S和MKN-74细胞来源于非硬化性癌。通过计算癌细胞的数量来确定Ki23057对细胞生长的影响。同时检测Ki23057对胃癌细胞丝裂原活化蛋白激酶和磷脂酰肌醇3激酶信号转导通路及细胞凋亡途径的影响。在体内实验中，Ki23057被口服到腹膜播散的小鼠模型中。结果：OCUM-2MD3和OCUM-8细胞有K-Samii扩增，而MKN-7、MKN-45和MKN-74细胞未见K-Samii扩增。Ki23057对硬化性胃癌细胞有明显的抑制作用，但对非硬化性胃癌细胞的增殖无明显影响。Ki23057使K-Samii/FGF-R2、细胞外信号调节激酶和Akt的磷酸化水平降低，并增加了硬癌细胞的凋亡率。口服Ki23057组与对照组比较差异有统计学意义(P
Background & Aims: Scirrhous gastric carcinoma carries the highest mortality of all gastric cancers. The poor prognosis is reported to be associated with K-samII amplification, which encodes fibroblast growth factor receptor type 2 (FGF-R-2). Ki23057, a newly developed small molecule-acting K-samII/FGF-R-2 autophosphorylation inhibitor, is a tyrosine kinase inhibitor that competes with adenosine triphosphate for the binding site. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-4S, and MKN-74 cells were derived from nonscirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the mitogen-activated protein kinase and phosphatidylinositol 3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells but not nonscirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, extracellular signal-regulated kinase, and Akt and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (P