Novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor as treatment for hepatocellular carcinoma. Issue 8 (25th June 2015)

• Record Type: Journal Article
• Authors: Nakao, Keisuke; Tanaka, Shinji; Miura, Tomoya; Sato, Kota; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Tanabe, Minoru
• Is Part Of: Cancer science. Volume 106:Issue 8(2015:Aug.)
• Page Start: 1016
• Page End: 1022
• Publication Date: 2015-06-25
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12701
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12701-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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. <italic>In vitro</italic> and <italic>in vivo</italic> 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 <italic>in vitro</italic> phosphorylation of histone H3 with induction of cell polyploidy and death in a dose‐dependent manner (IC<sub>50</sub> = 0.8–1.2 μM). In s.c. human HCC xenografts, remarkable inhibition of tumor growth was observed after JNJ‐28841072 treatment (<italic>P </italic>= 0.0005). In orthotopic liver xenografts, the treatment with JNJ‐28841072 significantly suppressed <italic>in vivo</italic> phosphorylation of histone H3 (<italic>P </italic>= 0.0008), vessel formation (<italic>P</italic> =<italic> </italic>0.018), normoxic area (<italic>P</italic> = 0.0001), and hepatoma growth (<italic>P </italic>=<italic> </italic>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.</p> </abstract>