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: Keisuke Nakao, Shinji Tanaka, Tomoya Miura, Kota Sato, Satoshi Matsumura, Arihiro Aihara, Yusuke Mitsunori, Daisuke Ban, Takanori Ochiai, Atsushi Kudo, Shigeki Arii, Minoru Tanabe
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 8 Pg. 1016-22 (Aug 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 26011703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Receptors, Vascular Endothelial Growth Factor
• AURKB protein, human
• Aurora Kinase B

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Aurora Kinase B (antagonists & inhibitors)
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Flow Cytometry
• Humans
• Immunohistochemistry
• Liver Neoplasms (pathology)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Xenograft Model Antitumor Assays