Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China.
J Transl Med. 2012 Dec 10;10:245. doi: 10.1186/1479-5876-10-245.
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.
多韦替尼是一种针对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 的受体酪氨酸激酶（RTK）抑制剂。多韦替尼目前正在进行治疗肝细胞癌（HCC）的临床试验。
本研究使用五株 HCC 细胞系和五株内皮细胞系来验证多韦替尼的分子和细胞靶标。
在原位 HCC 模型中，肿瘤生长和肺转移明显受到抑制。免疫印迹显示，在已知的多韦替尼靶标中，只有两种 HCC 细胞系中表达 PDGFR-β，而五种内皮细胞系中有四种表达 PDGFR-β、FGFR-1 和 VEGFR-2。多韦替尼在 0.04 μmol/L 的药理学相关浓度下抑制内皮细胞增殖和迁移；在相同浓度下，它不能抑制 HCC 细胞的增殖或迁移。免疫组织化学分析表明，多韦替尼显著降低了异种移植瘤的微血管密度，抑制了 HCC 细胞的增殖并诱导其凋亡。
我们的研究结果表明，多韦替尼通过抗血管生成机制抑制 HCC 的生长和转移，而不是直接靶向 HCC 细胞。
