title: Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.
abstract: OBJECTIVE
  Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells.
  
  
  METHODS
  Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects.
  
  
  RESULTS
  Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice.
  
  
  CONCLUSIONS
  Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients with poor liver tolerance.
authors.affiliation: Department of Oncology, Wuhan General Hospital of Guangzhou Command, Wuhan, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bicheng
authors.initials: B
authors.lastname: Zhang
authors.forename: Anran
authors.initials: A
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jianfei
authors.initials: J
authors.lastname: Gao
authors.forename: Dianchun
authors.initials: D
authors.lastname: Fang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Rao
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome; D024482:Vitamin K 2 / Q000008:administration & dosage*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D024482:Vitamin K 2; D009536:Niacinamide; D000077157:Sorafenib