Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.
Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.
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DOI：
10.1111/j.1872-034x.2012.01113.x
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Ho M
中科院分区：
文献类型：
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作者：
Gauthier A;Ho M
索拉非尼是目前批准用于治疗晚期肝细胞癌的第一种也是唯一一种口服药物。然而，人们对索拉非尼治疗提出了担忧，包括获得性耐药性。本综述基于实验室和临床研究中获得的数据，对索拉非尼治疗肝细胞癌的作用进行了综述。已发现支持索拉非尼治疗的三种潜在机制。首先，索拉非尼通过抑制丝裂原活化蛋白激酶(MAPK)通路中的BRAF和Raf1/c-Raf丝氨酸/苏氨酸激酶的磷酸化来抑制肝癌细胞的增殖。其次，索拉非尼通过降低肿瘤细胞中elF4E的磷酸化和下调Mcl-1水平来诱导细胞凋亡。第三，索拉非尼通过灭活血管内皮生长因子受体(VEGFR-2和VEGFR-3)和血小板衍生生长因子受体-β(PDGFR-β)来预防肿瘤相关的血管生成。临床试验已经证明了索拉非尼的有效性和相对安全性，因此该药用于不能切除的肝癌。然而，许多患者可能对索拉非尼产生获得性耐药性，因此他们对索拉非尼的反应最终会消失。索拉非尼可能会诱导自噬，从而导致细胞凋亡。然而，自噬也会导致抗药性。许多研究已经将索拉非尼与其他治疗方法结合起来，以努力增加其效果，减少必要的剂量，或克服耐药性。迫切需要研究索拉非尼与细胞分子和其他药物相互作用的机制，以提高其疗效并降低肝癌患者的耐药性。
Sorafenib is the first and only orally administered drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c-Raf serine/threonine kinase phosphorylation in the mitogen activated protein kinase (MAPK) pathway. Second, sorafenib induces apoptosis by reducing elF4E phosphorylation and down-regulating Mcl-1 levels in tumor cells. Third, sorafenib prevents tumor-associated angiogenesis by inactivating vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-3) and the platelet-derived growth factor receptor-β (PDGFR-β). Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in un-resectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dosage, or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.