Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584
Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584
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DOI：
10.1158/0008-5472.can-04-3462
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Fan, ST
中科院分区：
文献类型：
--
作者：
Liu, YQ;Poon, RT;Fan, ST
血管内皮生长因子（VEGF）在肝癌血管生成中起重要作用。抑制VEGF受体理论上可以减少肝细胞癌中的血管生成和肿瘤生长，但这仍有待实验研究证明。本研究检查了PTK 787/ZK 222584（PTK 787）（一种VEGF受体酪氨酸激酶抑制剂）在荷人肝细胞癌异种移植物裸鼠中的血管生成依赖性和血管生成非依赖性活性。还研究了PTK 787对人肝癌细胞系增殖、凋亡和细胞周期分布的体外影响。PTK 787经口给药导致裸鼠肝细胞癌异种移植瘤的肿瘤体积和微血管形成显著减少。PTK 787以剂量依赖性方式抑制肿瘤细胞增殖，并在体内和体外诱导肿瘤细胞凋亡。促凋亡反应与Bcl-2和BCI-x（L）表达的下调以及caspase-3裂解的诱导相关。此外，PTK 787诱导肝细胞癌细胞生长停滞，这与G阻滞和部分G（2）-M阻滞相关。这种效应与p21（WAFI/CIPI）（p21）和p27（KIPI）（p27）蛋白表达的增加相关。总之，本研究表明，PTK 787通过抗血管生成作用和对肿瘤细胞增殖和凋亡的直接作用，是肝细胞癌中肿瘤生长的强效抑制剂。我们的数据表明，阻断VEGF受体可能为人肝细胞癌提供一种有效的治疗方法。
Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis of hepatocellular carcinoma. Inhibition of VEGF receptors could theoretically reduce angiogenesis and tumor growth in hepatocellular carcinoma, but this remains to be proven with an experimental study. This study examined the angiogenesis-dependent and angiogenesis-independent activities of PTK787/ZK222584 (PTK787), a tyrosine kinase inhibitor of VEGF receptors, in nude mice bearing human hepatocellular carcinoma xenografts. The in vitro effects of PTK787 on proliferation, apoptosis, and cell cycle distribution in human hepatocellular carcinoma cell lines were also studied. Oral administration of PTK787 resulted in a significant reduction in tumor volume and microvessel formation of hepatocellular carcinoma xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dosedependent manner and also induced tumor cells to undergo apoptosis both in vivo and in vitro. The proapoptotic response was associated with down-regulation of Bcl-2 and BCI-x(L) expression and induction of cleavage of caspase-3. In addition, PTK787 induced growth arrest in hepatocellular carcinoma cells, which was associated with G, arrest and partial G(2)-M block. This effect correlated with an increase in p21(WAFI/CIPI) (p21) and p27(KIPI) (p27) protein expression. In conclusion, this study showed that PTK787 is a potent inhibitor of tumor growth in hepatocellular carcinoma by both antiangiogenic effect and direct effects on tumor cell proliferation and apoptosis. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human hepatocellular carcinoma.