Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.
Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.
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多韦替尼优先针对内皮细胞而不是癌细胞来抑制肝细胞癌的生长和转移
DOI：
10.1186/1479-5876-10-245
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发表时间：
2012-12-10
影响因子：
7.4
通讯作者：
Guo RP
中科院分区：
文献类型：
--
作者：
Chen ZY;Shi M;Peng LX;Wei W;Li XJ;Guo ZX;Li SH;Zhong C;Qian CN;Guo RP
Dovitinib是一种受体酪氨酸激酶（RTK）抑制剂，靶向血管内皮生长因子受体、成纤维细胞生长因子受体和血小板衍生生长因子受体β。Dovitinib目前正在进行治疗肝细胞癌（HCC）的临床试验。在这项研究中，我们使用了五种HCC细胞系和五种内皮细胞系来验证dovitinib的分子和细胞靶点。在原位HCC模型中，肿瘤生长和肺转移被显著抑制。免疫印迹显示，在已知的dovitinib靶点中，只有PDGFR-β在两种HCC细胞系中表达，而五种内皮细胞系中有四种表达PDGFR-β、FGFR-1和VEGFR-2。Dovitinib在0.04 μmol/L浓度下可抑制内皮细胞增殖和运动，这是一个显著相关的浓度;在相同浓度下，它不能抑制HCC细胞的增殖或运动。免疫组织化学分析显示，dovitinib显著降低异种移植肿瘤的微血管密度，抑制HCC细胞的增殖并诱导细胞凋亡。我们的研究结果表明，dovitinib抑制肝癌生长和转移优先通过抗血管生成机制，而不是通过直接靶向肝癌细胞。
Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.
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影响因子：
5.8
作者：
Chen, Kuen-Feng;Chen, Hui-Ling;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
5.7
作者：
Taeger, Johannes;Moser, Christian;Lang, Sven A.
通讯作者：
Lang, Sven A.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
6.4
作者：
Maass, Thorsten;Thieringer, Florian R.;Kanzler, Stephan
通讯作者：
Kanzler, Stephan
影响因子：
11.2
作者：
Franses JW;Edelman ER
通讯作者：
Edelman ER