J Cancer 2018; 9(5):914-922. doi:10.7150/jca.22329

Research Paper

Targeting hepatocarcinogenesis model in C56BL6 mice with pan-aurora kinase inhibitor Danusertib

Paschalis Gavriilidis1,8, Theofilos Poutahidis2, Alexander Giakoustidis5, Kali Makedou4, Katerina Angelopoulou3, Alexander Hardas2, Paola Andreani6, Argyro Zacharioudaki7, George Saridis2, Athanasios Gargavanis8, Eleni Louri5, Nikolaos Antoniadis8, Eleftheria Karampela7, Nikolaos Psychalakis7, Antonios Michalopoulos9, Apostolos Papalois7, Stavros Iliadis4, Satvinder Mudan5, Daniel Azoulay6, Dimitrios Giakoustidis8✉

1. Department of Hepato-Pancreato-Biliary and Liver Transplant surgery, Queen Elizabeth University Hospitals Birmingham NHS Foundation Trust, B15 1NU, UK.
2. Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki.
3. Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki.
4. Laboratory of Biochemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki.
5. Academic Department of Surgery, The Royal Marsden Hospital, London, UK.
6. Service de Chirurgie Digestive et Hépatobiliaire, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris-Université Paris-Est, Créteil, France.
7. Experimental and Research Center ELPEN Pharmaceuticals, Athens, Greece.
8. Division of Transplant Surgery, Department of Surgery, School of Medicine, Faculty of Health Sciences, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece.
9. Propaedeutic Division of Surgery, Department of Surgery School of Medicine, Faculty of Health Sciences, Aristotle University and AHEPA University Hospital, Thessaloniki, Greece.

Abstract

Background: To elucidate the expression of Aurora kinases (AURK) and the anticancer effects of pan-aurora kinase inhibitor Danusertib in hepatocarcinogenesis model in C56Bl6 mice.

Methods: Thirty mice C56Bl6 were randomly divided into Group A or control, Group B animals who underwent experimental hepatocarcinogenesis with diethylnitrosamine (DEN), and Group C animals with DEN-induced hepatocarcinogenenesis that treated with pan-aurora kinase inhibitor Danusertib. Primary antibodies for immunochistochemistry (IHC) included rabbit antibodies against Ki-67, DKK1, INCENP, cleaved caspase-3, NF-κB p65, c-Jun, β-catenin. Hepatocyte growth factor receptor (C-MET/HGFR) and Bcl-2 antagonist of cell death (BAD) serum levels were determined using a quantitative sandwich enzyme immunoassay technique.

Results: Inhibition of AURK reduced the number of DEN-induced liver tumours. Apoptosis and proliferation was very low in both DEN-induced and anti- AURK groups respectively. The hepatocellular adenoma cells of DEN-treated mice uniformly had ample nuclear INCENP whereas in anti- AURK markedly decreased. Expression of β-catenin, NF-kB and c-Jun did not differ in liver tumors of both AURK -depleted and non-depleted mice.

Conclusions: Depletion of AURK reduced the number of DEN-induced hepatic tumours. However, their size did not differ significantly between the groups.

Keywords: Hepatocarcinogenesis, Hepatocellular cancer, diethylnitrosamine, aurora kinases, danusertib

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How to cite this article:
Gavriilidis P, Poutahidis T, Giakoustidis A, Makedou K, Angelopoulou K, Hardas A, Andreani P, Zacharioudaki A, Saridis G, Gargavanis A, Louri E, Antoniadis N, Karampela E, Psychalakis N, Michalopoulos A, Papalois A, Iliadis S, Mudan S, Azoulay D, Giakoustidis D. Targeting hepatocarcinogenesis model in C56BL6 mice with pan-aurora kinase inhibitor Danusertib. J Cancer 2018; 9(5):914-922. doi:10.7150/jca.22329. Available from http://www.jcancer.org/v09p0914.htm