title: Synergistic effects of the combination of β-ionone and sorafenib on metastasis of human hepatoma SK-Hep-1 cells.
abstract: The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and β-ionone (BI), a precursor of carotenoids. We found that SF (1 μM) in combination with BI (1 μM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP-2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 μM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, 500 Lioufeng Road, Wufeng, Taichung 41354, Taiwan. cshuang@asia.edu.tw
authors.forename: Chin-Shiu
authors.initials: CS
authors.lastname: Huang
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lyu
authors.forename: Miao-Lin
authors.initials: ML
authors.lastname: Hu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D045792:Norisoprenoids / Q000494:pharmacology / Q000627:therapeutic use*; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000077157:Sorafenib; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D001557:Benzenesulfonates; D045792:Norisoprenoids; D010671:Phenylurea Compounds; D011725:Pyridines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D009536:Niacinamide; D000077157:Sorafenib; C008157:beta-ionone; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins