title: Digitoxin synergizes with sorafenib to inhibit hepatocelluar carcinoma cell growth without inhibiting cell migration.
abstract: Sorafenib is a chemotherapeutic agent approved for the treatment of hepatocellular carcinoma (HCC) in China. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers, but not in HCC. The aim of the present study was to evaluate the combinational effect of sorafenib and digitoxin on the treatment of HCC and to investigate the relevant molecular mechanisms of action that underlie these effects. The proliferation, cell death and migration of HCC cell lines, HepG2 and BEL‑7402, were examined using MTT, acridine orange/ethidium bromide staining and scratch wound healing assays, respectively. In addition, alterations in the expression of phosphorylated-extracellular signal-regulated kinase (ERK), hypoxia‑inducible factor 1‑α (HIF‑1α), hypoxia‑inducible factor 2‑α (HIF‑2α) and vascular endothelial growth factor (VEGF) were measured prior to and following drug application using western blot analysis. Digitoxin and sorafenib synergistically inhibited cell viability, but did not inhibit migration, which was potentially mediated by suppression of ERK and hypoxia signaling. In downstream signaling pathways, the activity of ERK was synergistically suppressed by combinatorial treatment of HepG2 and BEL‑7402 cells with sorafenib and digitoxin. In addition, the expression of HIF‑1α, HIF‑2α and VEGF was synergistically downregulated by combinational treatment.
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Libin
authors.initials: L
authors.lastname: Guo
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Meng
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, P.R. China.
authors.forename: Henrique
authors.initials: H
authors.lastname: Neves
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Peng-Chen
authors.initials: PC
authors.lastname: Chen
authors.affiliation: The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Yide
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, P.R. China.
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004074:Digitoxin / Q000494:pharmacology*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D002316:Cardiotonic Agents; D004074:Digitoxin; D048049:Extracellular Signal-Regulated MAP Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1