{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:13:23Z","timestamp":1784261603895,"version":"3.55.0"},"reference-count":30,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,12,5]],"date-time":"2020-12-05T00:00:00Z","timestamp":1607126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide. Sorafenib is the first\u2010line drug approved by the United States Food and Drug Administration for HCC. However, the acquired resistance to sorafenib reduces its beneficial effects and limits clinical use. In this study, we established a sorafenib\u2010resistant HCC cell line HepG2\u2010SR by low\u2010concentration gradient induction. Compared with the parental cell HepG2, the proliferation and anti\u2010apoptosis were increased in drug\u2010resistant cell HepG2\u2010SR. Thorough comparisons of the molecular changes between parental HepG2 and sorafenib\u2010resistant HepG2\u2010SR cells indicated that the Notch signaling pathway and PI3K\/Akt signaling pathway were associated with sorafenib resistance mechanisms. Notch1 and Akt were upregulated in sorafenib\u2010resistant cells. However, we surprisingly found that valproic acid (VPA) combined with sorafenib could enhance the sensitivity of drug\u2010resistant cells and reverse the increased levels of Notch1 and Akt in sorafenib\u2010resistant HCC cells. Moreover, Akt inhibitor could suppress Notch1 expression, whereas the level of Akt phosphorylation decreased along with increasing dose of Notch inhibitor. Besides, we found that knockdown of Akt resulted in Notch1 reduction, whereas Notch1 reduction also led to a significant reduction in the phosphorylation of Akt. Collectively, our results indicated that Notch1 and Akt might play vital roles in sorafenib resistance in HCC cells and VPA might overcome the drug resistance to enhance the sensitivity of HCC cells to sorafenib through suppressing Notch\/Akt signaling pathway. VPA combined with sorafenib may provide a potential targeting therapeutic regimen for clinically to solve the problem of sorafenib resistance.<\/jats:p>","DOI":"10.1111\/fcp.12608","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T05:18:21Z","timestamp":1601875101000},"page":"690-699","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Valproic acid reverses sorafenib resistance through inhibiting activated Notch\/Akt signaling pathway in hepatocellular carcinoma"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9439-4172","authenticated-orcid":false,"given":"Xu","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacy The Fifth People\u2019s Hospital of Shanghai Fudan University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-1335","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Fifth People\u2019s Hospital of Shanghai Fudan University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-2607","authenticated-orcid":false,"given":"Qing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Fifth People\u2019s Hospital of Shanghai Fudan University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5879-1621","authenticated-orcid":false,"given":"Guangchun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Fifth People\u2019s Hospital of Shanghai Fudan University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21262"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/21691401.2018.1543195"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.02.010"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1377"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61285-9"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70285-7"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708857"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-015-2020-4"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-017-0647-5"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2017.08.002"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000447912"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-016-1494-0"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/2930414"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S110425"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.07.005"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.12135"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm754"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200811141"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871520615666150202102809"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2007.08.001"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.06.019"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25206"},{"key":"e_1_2_7_24_1","first-page":"2503","article-title":"Combination of sorafenib and Valproic acid synergistically induces cell apoptosis and inhibits hepatocellular carcinoma growth via down\u2010regulating Notch3 and pAkt","volume":"7","author":"Zhu W.","year":"2017","journal-title":"Am. 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