Targeting Na<sup>+</sup>/K<sup>+</sup>‐ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma
Songpeng Yang, Shu Yang, Hongying Zhang, Hui Hua, Qingbin Kong, Jiao Wang, Yangfu Jiang
Abstract
Background and Purpose The 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 Approach We 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 Results Berbamine 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 growth in vivo . Conclusion and Implications Berbamine 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.