Oncotarget

Research Papers:

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension

Frank Erhard Uschner, Florian Schueller, Ivelina Nikolova, Sabine Klein, Robert Schierwagen, Fernando Magdaleno, Stefanie Gröschl, Sven Loosen, Thomas Ritz, Christoph Roderburg, Michael Vucur, Glen Kristiansen, Twan Lammers, Tom Luedde and Jonel Trebicka _

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Oncotarget. 2018; 9:36220-36237. https://doi.org/10.18632/oncotarget.26333

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Abstract

Frank Erhard Uschner1,9, Florian Schueller2, Ivelina Nikolova1, Sabine Klein1,3,9, Robert Schierwagen1, Fernando Magdaleno1, Stefanie Gröschl1, Sven Loosen2, Thomas Ritz2, Christoph Roderburg2, Michael Vucur2, Glen Kristiansen4, Twan Lammers5, Tom Luedde2,* and Jonel Trebicka1,6,7,8,9,*

1Department of Internal Medicine I, University of Bonn, Bonn, Germany

2Department of Internal Medicine III, University of Aachen, Aachen, Germany

3Institute of Cellular Medicine, Fibrosis Research Group, Newcastle upon Tyne, United Kingdom

4Department of Pathology, University of Bonn, Bonn, Germany

5Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, University of Aachen, Aachen, Germany

6Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark

7European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain

8Institute for Bioengineering of Catalonia, Barcelona, Spain

9Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany

*These authors have contributed equally to this work

Correspondence to:

Jonel Trebicka, email: [email protected]

Keywords: fibrosis; cirrhosis; inflammation; angiogenesis; portal hypertension

Received: June 19, 2018     Accepted: October 24, 2018     Published: November 16, 2018

ABSTRACT

Background and Aims: Angiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC.

Methods: Fibrosis (in vivo and in vitro), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl4, partial portal vein ligation) after acute and chronic treatment with regorafenib.

Results: Long-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed.

Discussion: Regorafenib might be especially suitable as therapy in patients with PHT and preserved liver function.


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