title: Synergistic effect of sorafenib and vitamin K on suppression of hepatocellular carcinoma cell migration and metastasis.
abstract: Vitamin K plays a role in controlling cell growth. Anti-angiogenic effects of sorafenib lead to impairment of vitamin K uptake and induction of des-γ-carboxyprothrombin release by hepatocellular carcinoma (HCC) cells. We examined sorafenib and vitamin K individually and in combination regarding their ability to suppress migration and metastatic potential of HCC cells. HepG2 cells (HCC cell line) were treated with hepatocyte growth factor (HGF). E-Cadherin expression, phospho-MET (p-MET), and phospho-extracellular signal-regulated kinase (p-ERK) levels and cell migration were evaluated. HGF-stimulated HepG2 cells, which were treated with a combination of sorafenib and vitamin K, showed significantly increased expression of E-cadherin and impairment of migration ability compared to when treated with either agent alone. This combination therapy also induced marked inhibition of epithelial-mesenchymal transition phenotype; inhibition of HGF-stimulated cell proliferation, invasion and migration; and inhibition of HGF/c-MET signaling pathway. Levels of p-MET and p-ERK were also significantly reduced by this combination. Our experimental study demonstrated that sorafenib and vitamin K can function synergistically to inhibit the migration and proliferation of HCC cells. Combination therapy with sorafenib and vitamin K appears to be worthy of clinical trial with expectation of synergistic therapeutic effects.
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Tae-Yong
authors: TY
authors: Ha
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea shwang@amc.seoul.kr.
authors: Shin
authors: S
authors: Hwang
authors: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Hea-Nam
authors: HN
authors: Hong
authors: Department of Surgery, Kosin University Gospel Hospital, Busan, Republic of Korea.
authors: Young-Il
authors: YI
authors: Choi
authors: Department of Surgery, Korea University Ansan Hospital, Gyeongi-do, Republic of Korea.
authors: Sam-Youl
authors: SY
authors: Yoon
authors: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: You-Jin
authors: YJ
authors: Won
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Gi-Won
authors: GW
authors: Song
authors: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Nayoung
authors: N
authors: Kim
authors: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Eunyoung
authors: E
authors: Tak
authors: Department of Oncology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Baek-Yeol
authors: BY
authors: Ryoo
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib; D014812:Vitamin K / Q000008:administration & dosage*
chemical_list: D010671:Phenylurea Compounds; D014812:Vitamin K; D009536:Niacinamide; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib
keywords: Cadherin; cell migration; des-γ-carboxyprothrombin; hepatocellular carcinoma; metastasis; side-effect