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The response to sorafenib varies among hepatocellular carcinoma patients and many of the responders suffer from reduced sensitivity after long\u2010term treatment. This study aims to explore a novel strategy to potentiate or maximize the anti\u2010hepatocellular carcinoma effects of sorafenib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We used hepatocellular carcinoma cell lines, western blotting, various antagonists, siRNA and tumour xenografts mouse model to determine the anti\u2010 hepatocellular carcinoma effects of sorafenib in combination with berbamine or other Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010ATPase ligands.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Berbamine and the cardiotonic steroid, ouabain, synergize with sorafenib to inhibit hepatocellular carcinoma cells growth. Mechanistically, berbamine induces Src phosphorylation in Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010ATPase\u2010dependent manner, leading to the activation of p38MAPK and EGFR\u2010ERK pathways. The Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010ATPase ligand ouabain also induces Src, EGFR, type I insulin\u2010like 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\u2010na\u00efve and sorafenib\u2010resistant hepatocellular carcinoma cells growth. Co\u2010treatment of hepatocellular carcinoma cells with berbamine and sorafenib significantly induces cell death and significantly inhibits hepatocellular carcinoma xenografts growth\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      Berbamine or other Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010ATPase ligands have a potential for improving sorafenib responsiveness in hepatocellular carcinoma. Targeting Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \u2010ATPase represents a novel strategy to potentiate the anti\u2010 hepatocellular carcinoma effects of sorafenib.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15616","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T16:45:43Z","timestamp":1625676343000},"page":"4389-4407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting Na\n                    <sup>+<\/sup>\n                    \/K\n                    <sup>+<\/sup>\n                    \u2010ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-8773","authenticated-orcid":false,"given":"Songpeng","family":"Yang","sequence":"first","affiliation":[{"name":"Laboratory of Oncogene, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogene, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogene, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Hua","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbin","family":"Kong","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogene, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-2651","authenticated-orcid":false,"given":"Yangfu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogene, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14563"},{"issue":"1","key":"e_1_2_12_3_1","first-page":"S297","article-title":"The concise guide to pharmacology 2019\/20: Enzymes","volume":"176","author":"Alexander S. 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