Ha, Tae-Yong; Hwang, Shin; Hong, Hea-Nam; Choi, Young-Il; Yoon, Sam-Youl; Won, You-Jin; Song, Gi-Won; Kim, Nayoung; Tak, Eunyoung; Ryoo, Baek-Yeol
Anticancer research
2015Apr ; 35 ( 4 ) :1985-95.
PMID : 25862851
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Ha, Tae-Yong - Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hwang, Shin - Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea shwang@amc.seoul.kr.
Hong, Hea-Nam - Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Choi, Young-Il - Department of Surgery, Kosin University Gospel Hospital, Busan, Republic of Korea.
Yoon, Sam-Youl - Department of Surgery, Korea University Ansan Hospital, Gyeongi-do, Republic of Korea.
Won, You-Jin - Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Song, Gi-Won - Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Kim, Nayoung - Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Tak, Eunyoung - Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Ryoo, Baek-Yeol - Department of Oncology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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. CI - Copyright??2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
keyword
Cadherin; cell migration; des-gamma-carboxyprothrombin; hepatocellular carcinoma; metastasis; side-effect
MESH
Carcinoma, Hepatocellular/*drug therapy/pathology, Cell Movement/drug effects, Cell Proliferation/drug effects, Drug Synergism, Hep G2 Cells, Hepatocyte Growth Factor/administration & dosage, Humans, Liver Neoplasms/*drug therapy/pathology, Niacinamide/administration & dosage/*analogs & derivatives, Phenylurea Compounds/*administration & dosage, Vitamin K/*administration & dosage
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