The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma.

Abstract

BACKGROUND & AIMS:

We previously identified that high Aurora B expression was associated with hepatocellular carcinoma (HCC) recurrence due to tumor dissemination. In this preclinical study, a novel inhibitor of Aurora B kinase was evaluated as a treatment for human HCC.

METHODS:

AZD1152 is a selective inhibitor of Aurora B kinase. Twelve human HCC cell lines were analyzed for Aurora B kinase expression and the in vitro effects of AZD1152. The in vivo effects of AZD1152 were analyzed in a subcutaneous xenograft model and a novel orthotopic liver xenograft model.

RESULTS:

Aurora B kinase expression varied among the human HCC cell lines and was found to correlate with inhibition of cell proliferation, accumulation of 4N DNA, and the proportion of polyploid cells following administration of AZD1152-hydroxyquinazoline-pyrazol-anilide (AZD1152-HQPA). AZD1152-HQPA suppressed histone H3 phosphorylation and induced cell death in a dose-dependent manner. Growth of subcutaneous human HCC xenografts was inhibited by AZD1152 administration. In an orthotopic hepatoma model, treatment with AZD1152 significantly decelerated tumor growth and increased survival. Pharmacobiological analysis revealed that AZD1152 induced the rapid suppression of phosphohistone H3, followed by cellular apoptosis in the liver tumors but not in the normal tissues of the orthotopic models.

CONCLUSIONS:

Our preclinical studies indicate that AZD1152 is a promising novel therapeutic approach for the treatment of HCC.

• Authors: Arihiro Aihara, Shinji Tanaka, Mahmut Yasen, Satoshi Matsumura, Yusuke Mitsunori, Ayano Murakata, Norio Noguchi, Atsushi Kudo, Noriaki Nakamura, Koji Ito, Shigeki Arii
• Journal: Journal of hepatology (J Hepatol) Vol. 52 Issue 1 Pg. 63-71 (Jan 2010) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 19913935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
• Histones
• Organophosphates
• Quinazolines
• AURKB protein, human
• Aurkb protein, mouse
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Aurora Kinase B
• Aurora Kinases
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Histones (metabolism)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Organophosphates (therapeutic use)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Quinazolines (therapeutic use)
• Treatment Outcome
• Xenograft Model Antitumor Assays