索拉非尼对人肝内胆管癌细胞的体外和体内抗肿瘤活性。
Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells.
机构信息
Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan.
出版信息
J Gastroenterol. 2011 Jun;46(6):779-89. doi: 10.1007/s00535-011-0380-3. Epub 2011 Feb 18.
BACKGROUND
Intrahepatic cholangiocarcinoma (ICC) is rising in clinical importance due to the increasing incidence worldwide, poor prognosis, and suboptimal response to therapies. New effective therapeutic approaches are needed for improvement of treatment outcome. A recent study showed that sorafenib, a multikinase inhibitor that acts predominantly through inhibition of Raf kinase and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, exhibited potent antitumor activity in a preclinical model of cholangiocarcinoma cells.
METHOD
We tested the in vitro and in vivo antitumor activity of sorafenib against human ICC cell lines.
RESULTS
Treatment of ICC cells with sorafenib resulted in inhibition of proliferation and induction of apoptosis in the cell lines. In the cells treated with sorafenib, phosphorylation of mitogen-activated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK) and also interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) were inhibited in a dose-dependent manner. Down-regulation of the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) paralleled the reduced phosphorylation of STAT3. However, sorafenib induced no significant change in the cell cycle distribution and the expression levels of cyclin D1 and p27(Kip1) in the cells. For the in vivo antitumor activity, oral administration of sorafenib significantly inhibited the growth of subcutaneous tumors established in immunodeficient mice at doses of 10, 30, and 100 mg/kg. Moreover, administration of sorafenib (30 mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43 days in treated and vehicle-treated mice, respectively).
CONCLUSION
These results indicate that sorafenib is a potent agent that may provide a new therapeutic option for human ICC.
背景
由于全球范围内发病率的增加、预后不良以及对治疗的反应不佳，肝内胆管癌（ICC）在临床重要性方面不断上升。需要新的有效治疗方法来改善治疗效果。最近的一项研究表明，索拉非尼是一种多激酶抑制剂，主要通过抑制 Raf 激酶和血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）受体发挥作用，在胆管癌细胞的临床前模型中表现出强大的抗肿瘤活性。
方法
我们测试了索拉非尼对人 ICC 细胞系的体外和体内抗肿瘤活性。
结果
索拉非尼处理 ICC 细胞导致细胞系增殖受到抑制并诱导细胞凋亡。在用索拉非尼处理的细胞中，丝裂原活化蛋白激酶激酶（MEK）和丝裂原活化蛋白激酶（MAPK）的磷酸化以及白细胞介素 6 诱导的信号转导和转录激活因子 3（STAT3）的磷酸化呈剂量依赖性方式被抑制。抗凋亡蛋白髓样细胞白血病-1（Mcl-1）的下调与 STAT3 磷酸化的减少相平行。然而，索拉非尼在细胞中未引起细胞周期分布和细胞周期蛋白 D1 和 p27（Kip1）表达水平的显著变化。对于体内抗肿瘤活性，口服索拉非尼以 10、30 和 100mg/kg 的剂量显著抑制免疫缺陷小鼠皮下肿瘤的生长。此外，与未治疗的动物相比，索拉非尼（30mg/kg）给药可显著延长患有腹腔播散性 ICC 的动物的存活时间（分别为 76 天和 43 天）。
结论
这些结果表明，索拉非尼是一种有效的药物，可为人类 ICC 提供新的治疗选择。
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