{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:05:53Z","timestamp":1789563953905,"version":"build-2803163510"},"reference-count":74,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK\/ERK\/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.<\/jats:p>","DOI":"10.3390\/ijms23158083","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T12:53:45Z","timestamp":1658494425000},"page":"8083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK\/ERK\/Stat3 Axis in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"23","author":[{"given":"Sumit","family":"Siddharth","sequence":"first","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3293-7220","authenticated-orcid":false,"given":"Panjamurthy","family":"Kuppusamy","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qitong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4856-2630","authenticated-orcid":false,"given":"Arumugam","family":"Nagalingam","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj K.","family":"Saxena","sequence":"additional","affiliation":[{"name":"National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipali","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1053\/j.gastro.2018.08.065","article-title":"Epidemiology and Management of Hepatocellular Carcinoma","volume":"156","author":"Kulik","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"705","DOI":"10.7326\/0003-4819-144-10-200605160-00004","article-title":"The prevalence of hepatitis C virus infection in the United States, 1999 through 2002","volume":"144","author":"Armstrong","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.cgh.2014.08.037","article-title":"Prevalence of suspected nonalcoholic fatty liver disease in Hispanic\/Latino individuals differs by heritage","volume":"13","author":"Kallwitz","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.cgh.2014.08.013","article-title":"Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population","volume":"13","author":"Mittal","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11894-019-0681-x","article-title":"The Epidemiology of Hepatocellular Carcinoma in the USA","volume":"21","author":"Kim","year":"2019","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jhep.2018.10.008","article-title":"Hepatocellular carcinoma in the setting of alcohol-related liver disease","volume":"70","author":"Nahon","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.cgh.2016.07.020","article-title":"Direct and Indirect Economic Burden of Chronic Liver Disease in the United States","volume":"15","author":"Stepanova","year":"2017","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1053\/j.gastro.2010.09.038","article-title":"Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study","volume":"140","author":"Williams","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1053\/j.gastro.2018.08.024","article-title":"Risk of Hepatocellular Cancer in Patients with Non-Alcoholic Fatty Liver Disease","volume":"155","author":"Kanwal","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cgh.2010.08.019","article-title":"Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma","volume":"9","author":"Yang","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1038\/bjc.2013.564","article-title":"Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy","volume":"109","author":"Chang","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/hep.27095","article-title":"HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV","volume":"60","author":"Kanwal","year":"2014","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.28535","article-title":"Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection","volume":"64","author":"Kanwal","year":"2016","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","article-title":"From NASH to HCC: Current concepts and future challenges","volume":"16","author":"Anstee","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1124\/molpharm.120.000223","article-title":"Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells","volume":"100","author":"Harati","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/dmrr.1291","article-title":"Diabetes mellitus and risk of hepatocellular carcinoma: A systematic review and meta-analysis","volume":"28","author":"Wang","year":"2012","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cgh.2005.12.007","article-title":"The association between diabetes and hepatocellular carcinoma: A systematic review of epidemiologic evidence","volume":"4","author":"Hampel","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.21037\/atm.2017.04.41","article-title":"Type 2 diabetes mellitus and risk of hepatocellular carcinoma: Spotlight on nonalcoholic fatty liver disease","volume":"5","author":"Mantovani","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ajg.2013.5","article-title":"Anti-diabetic medications and the risk of hepatocellular cancer: A systematic review and meta-analysis","volume":"108","author":"Singh","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/hep.29086","article-title":"AASLD guidelines for the treatment of hepatocellular carcinoma","volume":"67","author":"Heimbach","year":"2018","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.clinre.2015.07.008","article-title":"Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: A systematic review and meta-analysis","volume":"40","author":"Chen","year":"2016","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"(2012). EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J. Hepatol., 56, 908\u2013943.","DOI":"10.1016\/j.jhep.2011.12.001"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nrd2130","article-title":"Discovery and development of sorafenib: A multikinase inhibitor for treating cancer","volume":"5","author":"Wilhelm","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1470-2045(08)70285-7","article-title":"Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial","volume":"10","author":"Cheng","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3748\/wjg.v22.i1.407","article-title":"Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: A comprehensive review","volume":"22","author":"Han","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_30","first-page":"623","article-title":"Current Status of Sorafenib Use for Treatment of Hepatocellular Carcinoma","volume":"13","author":"Margaret","year":"2017","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"40","DOI":"10.4103\/1319-3767.37808","article-title":"Sorafenib in the treatment of advanced hepatocellular carcinoma","volume":"14","year":"2008","journal-title":"Saudi J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1136\/gutjnl-2011-301708","article-title":"Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: Population-based and in vitro studies","volume":"62","author":"Chen","year":"2013","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1038\/labinvest.3700355","article-title":"Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis","volume":"85","author":"Beckner","year":"2005","journal-title":"Lab. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1111\/j.1476-5381.2010.00762.x","article-title":"Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase-9 activation through a calcium and protein kinase Calpha-dependent pathway: Phorbol-12-myristate-13-acetate-induced\/extracellular signal-regulated kinase\/activator protein-1","volume":"160","author":"Hwang","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33743","DOI":"10.1038\/srep33743","article-title":"Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma","volume":"6","author":"Zhou","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.aohep.2019.10.005","article-title":"Metformin in the prevention of hepatocellular carcinoma in diabetic patients: A systematic review","volume":"19","author":"Cunha","year":"2020","journal-title":"Ann. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1007\/s00726-014-1838-4","article-title":"Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK\/JNK-mediated NF-\u03baB-dependent pathway that reduces uPA and MMP-9 expression","volume":"46","author":"Hsieh","year":"2014","journal-title":"Amino Acids"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1038\/s41388-018-0582-8","article-title":"The ERK and JNK pathways in the regulation of metabolic reprogramming","volume":"38","author":"Papa","year":"2019","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"Wagner","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S375","DOI":"10.1245\/s10434-011-1836-7","article-title":"The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection","volume":"19","author":"Chen","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tsai, M.-C., Yen, Y.-H., Chang, K.-C., Hung, C.-H., Chen, C.-H., Lin, M.-T., and Hu, T.-H. (2019). Elevated levels of serum urokinase plasminogen activator predict poor prognosis in hepatocellular carcinoma after resection. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6397-3"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3892\/ijo.2014.2419","article-title":"Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo","volume":"45","author":"Miyoshi","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13832","DOI":"10.18632\/oncotarget.14640","article-title":"Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway","volume":"8","author":"Tsai","year":"2017","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"116966","DOI":"10.1016\/j.lfs.2019.116966","article-title":"Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1\u03b1\/PFKFB3\/PFK1 pathway","volume":"239","author":"Hu","year":"2019","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s40262-015-0270-6","article-title":"A Comprehensive Review of Drug-Drug Interactions with Metformin","volume":"54","author":"Stage","year":"2015","journal-title":"Clin. Pharmacokinet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e00954","DOI":"10.1002\/prp2.954","article-title":"Ivermectin synergizes sorafenib in hepatocellular carcinoma via targeting multiple oncogenic pathways","volume":"10","author":"Lu","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Han, S., Lim, J.Y., Cho, K., Lee, H.W., Park, J.Y., Ro, S.W., Kim, K.S., Seo, H.R., and Kim, D.Y. (2022). Anti-Cancer Effects of YAP Inhibitor (CA3) in Combination with Sorafenib against Hepatocellular Carcinoma (HCC) in Patient-Derived Multicellular Tumor Spheroid Models (MCTS). Cancers, 14.","DOI":"10.3390\/cancers14112733"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1166\/jbn.2022.3279","article-title":"Nanoparticles Loaded with GSK1059615 Combined with Sorafenib Inhibited Programmed Cell Death 1 Ligand 1 Expression by Negatively Regulating the PI3K\/Akt\/NF-kappaB Pathway, Thereby Reversing the Drug Resistance of Hepatocellular Carcinoma to Sorafenib","volume":"18","author":"Zhou","year":"2022","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13919","DOI":"10.1080\/21655979.2022.2074616","article-title":"Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K\/Akt signaling pathway","volume":"13","author":"Wei","year":"2022","journal-title":"Bioengineered"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1080\/13543784.2021.1972969","article-title":"PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: How can they assist drug clinical trials?","volume":"31","author":"Rizzo","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"891008","DOI":"10.3389\/fphar.2022.891008","article-title":"Immune Checkpoint Inhibitors Plus an Anti-VEGF Antibody as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis and Cost-Effectiveness Analysis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9997","DOI":"10.1038\/s41598-018-28337-6","article-title":"Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: A proof of concept","volume":"8","author":"Tovoli","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kelley, R.K., Rimassa, L., Cheng, A.L., Kaseb, A., Qin, S., Zhu, A.X., Chan, S.L., Melkadze, T., Sukeepaisarnjaroen, W., and Breder, V. (2022). Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol.","DOI":"10.1016\/S1470-2045(22)00326-6"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3892\/ijo.2016.3799","article-title":"Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway","volume":"50","author":"Ling","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"179","DOI":"10.14701\/ahbps.2018.22.3.179","article-title":"Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines","volume":"22","author":"Chung","year":"2018","journal-title":"Ann. Hepatobiliary Pancreat. Surg."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"596655","DOI":"10.3389\/fcell.2020.596655","article-title":"Metformin Resensitizes Sorafenib-Resistant HCC Cells Through AMPK-Dependent Autophagy Activation","volume":"8","author":"Lai","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1111\/cas.12885","article-title":"Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30","volume":"107","author":"Guo","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1517\/14656566.2015.1102887","article-title":"Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib","volume":"16","author":"Marisi","year":"2015","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"297","DOI":"10.14701\/ahbps.2018.22.4.297","article-title":"Absence of antitumor effects of metformin in sorafenib-treated patients with hepatocellular carcinoma recurrence after hepatic resection and liver transplantation","volume":"22","author":"Chung","year":"2018","journal-title":"Ann. Hepatobiliary Pancreat. Surg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"165-e222","DOI":"10.1093\/oncolo\/oyab008","article-title":"Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH)","volume":"27","author":"Ostwal","year":"2022","journal-title":"Oncologist"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.3892\/ol.2016.5110","article-title":"The Ras\/Raf\/MEK\/ERK signaling pathway and its role in the occurrence and development of HCC","volume":"12","author":"Li","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.pharmthera.2013.10.001","article-title":"MEK in cancer and cancer therapy","volume":"141","author":"Neuzillet","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1091\/mbc.2.8.599","article-title":"Epidermal growth factor and transforming growth factor-alpha: Differential intracellular routing and processing of ligand-receptor complexes","volume":"2","author":"Ebner","year":"1991","journal-title":"Cell Regul."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/0046-8177(95)90275-9","article-title":"Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: Relative expression of transforming growth factor-alpha and its receptor in the different areas of tumor","volume":"26","author":"Morimitsu","year":"1995","journal-title":"Hum. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1038\/sj.onc.1208196","article-title":"Epidermal growth factor-induced hepatocellular carcinoma: Gene expression profiles in precursor lesions, early stage and solitary tumours","volume":"24","author":"Borlak","year":"2005","journal-title":"Oncogene"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ejca.2017.09.003","article-title":"Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale","volume":"86","author":"Faloppi","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/FPC.0b013e3283559b22","article-title":"Metformin pathways: Pharmacokinetics and pharmacodynamics","volume":"22","author":"Gong","year":"2012","journal-title":"Pharm. Genom."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Siddharth, S., Muniraj, N., Saxena, N.K., and Sharma, D. (2019). Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma. Cancers, 11.","DOI":"10.3390\/cancers11040453"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e70729","DOI":"10.7554\/eLife.70729","article-title":"Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression","volume":"10","author":"Siddharth","year":"2021","journal-title":"Elife"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"17943","DOI":"10.1038\/s41598-017-18190-4","article-title":"Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice","volume":"7","author":"Kuppusamy","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3727\/096504013X13786659070190","article-title":"Induction of apoptosis by 4-(3-(tert-butylamino)imidazo[1,2-\u03b1]pyridine-2-yl) benzoic acid in breast cancer cells via upregulation of PTEN","volume":"21","author":"Siddharth","year":"2013","journal-title":"Oncol. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"104118","DOI":"10.1016\/j.dib.2019.104118","article-title":"In vitro effects of resistin on epithelial to mesenchymal transition (EMT) in MCF-7 and MDA-MB-231 breast cancer cells\u2014qRT-PCR and Westen blot analyses data","volume":"25","author":"Avtanski","year":"2019","journal-title":"Data Brief"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.molonc.2016.04.003","article-title":"Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis","volume":"10","author":"Avtanski","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9712","DOI":"10.1158\/0008-5472.CAN-08-1952","article-title":"Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor","volume":"68","author":"Saxena","year":"2008","journal-title":"Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:54:52Z","timestamp":1760140492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,22]]},"references-count":74,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158083"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158083","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,22]]}}}