Targeting Na + /K + ‐ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma
Targeting Na + /K + ‐ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma
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小檗胺和哇巴因靶向 Na /K ATP 酶与索拉非尼协同抑制肝细胞癌
DOI：
10.1111/bph.15616
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发表时间：
2021
影响因子：
7.3
通讯作者：
Yangfu Jiang
中科院分区：
文献类型：
--
作者：
Songpeng Yang;Shu Yang;Hongying Zhang;Hui Hua;Qingbin Kong;Jiao Wang;Yangfu Jiang
背景与目的多激酶抑制剂索拉非尼是治疗晚期肝细胞癌的一线药物。肝细胞癌患者对索拉非尼的反应各不相同，许多应答者在长期治疗后敏感性降低。本研究旨在探索一种新的策略来增强或最大化索拉非尼抗肝细胞癌的作用。实验方法：我们使用肝癌细胞系、western blotting、各种拮抗剂、siRNA和肿瘤异种移植小鼠模型来确定索拉非尼与小檗碱或其他Na+/K+‐atp酶配体联合使用的抗肝癌作用。关键结果：小檗碱和心脏强直类固醇乌阿巴因与索拉非尼协同抑制肝癌细胞生长。在机制上，小檗胺以Na+/K+‐atp酶依赖的方式诱导Src磷酸化，导致p38MAPK和EGFR‐ERK通路的激活。Na+/K+‐atp酶配体瓦巴因还可诱导肝癌细胞Src、EGFR、I型胰岛素样生长因子受体、ERK1/2和p38MAPK磷酸化。用Src或EGFR抑制剂治疗肝癌细胞可抑制小檗胺诱导的ERK1/2磷酸化。此外，索拉非尼抑制berbamine和ouabain诱导Src、p38MAPK、EGFR和ERK1/2磷酸化。重要的是，索拉非尼与berbamine或ouabain联合使用可协同抑制索拉非尼naïve和索拉非尼耐药肝细胞癌细胞的生长。用小檗胺和索拉非尼共同治疗肝癌细胞可显著诱导细胞死亡，并显著抑制肝癌异种移植物的体内生长。结论和意义小檗碱或其他Na+/K+‐atp酶配体有可能改善索拉非尼在肝细胞癌中的反应性。靶向Na+/K+ - atp酶是一种增强索拉非尼抗肝细胞癌作用的新策略。
Background and PurposeThe multikinase inhibitor sorafenib is a first‐line drug for advanced hepatocellular carcinoma. The response to sorafenib varies among hepatocellular carcinoma patients and many of the responders suffer from reduced sensitivity after long‐term treatment. This study aims to explore a novel strategy to potentiate or maximize the anti‐hepatocellular carcinoma effects of sorafenib.Experimental ApproachWe used hepatocellular carcinoma cell lines, western blotting, various antagonists, siRNA and tumour xenografts mouse model to determine the anti‐ hepatocellular carcinoma effects of sorafenib in combination with berbamine or other Na+/K+‐ATPase ligands.Key ResultsBerbamine and the cardiotonic steroid, ouabain, synergize with sorafenib to inhibit hepatocellular carcinoma cells growth. Mechanistically, berbamine induces Src phosphorylation in Na+/K+‐ATPase‐dependent manner, leading to the activation of p38MAPK and EGFR‐ERK pathways. The Na+/K+‐ATPase ligand ouabain also induces Src, EGFR, type I insulin‐like growth factor receptor, ERK1/2 and p38MAPK phosphorylation in hepatocellular carcinoma cells. Treatment of hepatocellular carcinoma cells with Src or EGFR inhibitor inhibits the induction of ERK1/2 phosphorylation by berbamine. Moreover, sorafenib inhibits the induction of Src, p38MAPK, EGFR and ERK1/2 phosphorylation by berbamine and ouabain. Importantly, combination of sorafenib with berbamine or ouabain synergistically inhibits both sorafenib‐naïve and sorafenib‐resistant hepatocellular carcinoma cells growth. Co‐treatment of hepatocellular carcinoma cells with berbamine and sorafenib significantly induces cell death and significantly inhibits hepatocellular carcinoma xenografts growthin vivo.Conclusion and ImplicationsBerbamine or other Na+/K+‐ATPase ligands have a potential for improving sorafenib responsiveness in hepatocellular carcinoma. Targeting Na+/K+‐ATPase represents a novel strategy to potentiate the anti‐ hepatocellular carcinoma effects of sorafenib.