{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:14:49Z","timestamp":1784304889214,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21672041"],"award-info":[{"award-number":["21672041"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sorafenib (SF), a multi\u2010kinase inhibitor, is the first FDA\u2010approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. <jats:italic>Sophora alopecuroides<\/jats:italic> L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti\u2010tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A (<jats:bold>1<\/jats:bold>), sophoraflavanone G (<jats:bold>3<\/jats:bold>), and trifolirhizin (<jats:bold>17<\/jats:bold>) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC<jats:sub>50<\/jats:sub> of SF reduced by 5.8\u2010fold, 3.6\u2010fold, and 3.5\u2010fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds <jats:bold>3<\/jats:bold> or <jats:bold>17<\/jats:bold> combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial\u2010mediated apoptotic pathway, involving higher Bax\/Bcl\u20102 expressions with the activation of caspase\u20109 and \u20103, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co\u2010suppression of ERK and AKT signaling pathways. Furthermore, compound <jats:bold>3<\/jats:bold> significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid <jats:bold>3<\/jats:bold> and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.<\/jats:p>","DOI":"10.1002\/ptr.7637","type":"journal-article","created":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T04:11:08Z","timestamp":1664597468000},"page":"592-610","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Synergistic anticancer effect of flavonoids from <i>Sophora alopecuroides<\/i> with Sorafenib against hepatocellular carcinoma"],"prefix":"10.1002","volume":"37","author":[{"given":"Xiao\u2010Feng","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Pharmacy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong\u2010Lin","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery &amp; Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery &amp; Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Cheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery &amp; Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu\u2010Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery &amp; 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