Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT
Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT
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索拉非尼和水飞蓟宾联合治疗通过增强对 STAT3/ERK/AKT 磷酸化的抑制，协同靶向 HCC 细胞和癌症干细胞
DOI：
10.1016/j.ejphar.2018.05.027
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发表时间：
2018-08-05
影响因子：
5
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Mao, Jie;Yang, Hongbao;Yang, Yong
水飞蓟宾是水飞蓟中一种无毒的生物活性成分，具有抗氧化、抗炎等作用，在临床上被用作保肝药。本研究探讨了水飞蓟宾联合索拉非尼对肝癌细胞的杀伤作用。结果表明，水飞蓟宾联合索拉非尼可有效抑制各种肝癌细胞的增殖，并诱导明显的凋亡。在HCC皮下移植肿瘤模型中，与单一疗法相比，水飞蓟宾和索拉非尼的组合显著抑制肿瘤生长。如通过荧光染色和Western印迹所确定的，两种药物的组合抑制RAC-α丝氨酸/苏氨酸蛋白激酶（AKT）和信号转导子和转录激活子3（STAT 3）的磷酸化以及抗凋亡蛋白的表达，所述抗凋亡蛋白包括髓性白血病细胞分化蛋白Mcl-1（Mcl-1）和凋亡调节因子Bcl-2（Bcl-2），导致癌细胞死亡。我们还发现，该组合通过下调干细胞相关蛋白的表达来抑制HCC干细胞的形成和自我更新，例如同源框蛋白NANOG（Nanog）和Krueppel样因子4（Klf 4）。这些结果表明，水飞蓟宾提高了索拉非尼在肝癌治疗中的疗效，表明肝癌患者的临床有希望的治疗策略。
Silibinin, a nontoxic bioactive component in milk thistle, is used as a liver-protective drug in the clinic mainly because of its antioxidant and anti-inflammation activities. In this study, we studied the cytotoxic effects of silibinin combined with sorafenib on hepatocellular carcinoma (HCC). The results indicated that silibinin combined with sorafenib potently inhibited the proliferation of various HCC cells and induced significant apoptosis. In an HCC subcutaneous transplantation tumor model, the combination of silibinin and sorafenib significantly suppressed tumor growth compared with monotherapy. As determined by fluorescence staining and Western blots, the combination of the two drugs inhibited the phosphorylation of RAC-alpha serine/threonine-protein kinase (AKT) and signal transducer and activator of transcription 3 (STAT3) together with the expression of antiapoptotic proteins including myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and apoptosis regulator Bcl-2 (Bcl-2), resulting in the death of cancer cells. We also found that the combination inhibited the formation and self-renewal of HCC stem cells by down-regulating the expression of stemness-related proteins, such as Homeobox protein NANOG (Nanog) and Krueppel-like factor 4 (Klf4). These results suggested that silibinin improved the efficacy of sorafenib in HCC therapy, indicating a clinical promising therapeutic strategy for HCC patients.