title: Novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor as treatment for hepatocellular carcinoma.
abstract: We previously identified Aurora B kinase as the only independent factor predictive of the aggressive recurrence of hepatocellular carcinoma (HCC). In this preclinical study, JNJ-28841072, a novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor, was evaluated for treatment of HCC. In vitro and in vivo effects of JNJ-28841072 were analyzed using human HCC cell cultures and xenograft models. An orthotopic liver xenograft model was used for the pharmacobiological effects on Aurora kinase and vascularization in hepatic tumors. JNJ-28841072 suppressed in vitro phosphorylation of histone H3 with induction of cell polyploidy and death in a dose-dependent manner (IC50  = 0.8-1.2 μM). In s.c. human HCC xenografts, remarkable inhibition of tumor growth was observed after JNJ-28841072 treatment (P = 0.0005). In orthotopic liver xenografts, the treatment with JNJ-28841072 significantly suppressed in vivo phosphorylation of histone H3 (P = 0.0008), vessel formation (P = 0.018), normoxic area (P = 0.0001), and hepatoma growth (P = 0.038). Our preclinical studies indicate that JNJ-28841072 is a promising novel therapeutic approach for the treatment of HCC. It might be worthy of evaluation in further studies.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mitsunori
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; C576921:AURKB protein, human; D064107:Aurora Kinase B
keywords: Angiogenesis; Aurora; dual kinase inhibitor; hepatocellular carcinoma; molecularly targeted medicine