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, Jonel Trebicka*

*Kontaktforfatter for dette arbejde

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Resumé

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.

OriginalsprogEngelsk
TidsskriftOncotarget
Vol/bind9
Udgave nummer90
Sider (fra-til)36220-36237
ISSN1949-2553
DOI
StatusUdgivet - 1. nov. 2018

Fingeraftryk

Portal Hypertension
Hepatocellular Carcinoma
Portal Vein
Ligation
Liver
Liver Cirrhosis
Theoretical Models

Citer dette

Uschner, F. E., Schueller, F., Nikolova, I., Klein, S., Schierwagen, R., Magdaleno, F., ... Trebicka, J. (2018). The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension. Oncotarget, 9(90), 36220-36237. https://doi.org/10.18632/oncotarget.26333
Uschner, Frank Erhard ; Schueller, Florian ; Nikolova, Ivelina ; Klein, Sabine ; Schierwagen, Robert ; Magdaleno, Fernando ; Gröschl, Stefanie ; Loosen, Sven ; Ritz, Thomas ; Roderburg, Christoph ; Vucur, Michael ; Kristiansen, Glen ; Lammers, Twan ; Luedde, Tom ; Trebicka, Jonel. / The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension. I: Oncotarget. 2018 ; Bind 9, Nr. 90. s. 36220-36237.
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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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Uschner, FE, Schueller, F, Nikolova, I, Klein, S, Schierwagen, R, Magdaleno, F, Gröschl, S, Loosen, S, Ritz, T, Roderburg, C, Vucur, M, Kristiansen, G, Lammers, T, Luedde, T & Trebicka, J 2018, 'The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension', Oncotarget, bind 9, nr. 90, s. 36220-36237. https://doi.org/10.18632/oncotarget.26333

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension. / Uschner, Frank Erhard; Schueller, Florian; Nikolova, Ivelina; Klein, Sabine; Schierwagen, Robert; Magdaleno, Fernando; Gröschl, Stefanie; Loosen, Sven; Ritz, Thomas; Roderburg, Christoph; Vucur, Michael; Kristiansen, Glen; Lammers, Twan; Luedde, Tom; Trebicka, Jonel.

I: Oncotarget, Bind 9, Nr. 90, 01.11.2018, s. 36220-36237.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension

AU - Uschner, Frank Erhard

AU - Schueller, Florian

AU - Nikolova, Ivelina

AU - Klein, Sabine

AU - Schierwagen, Robert

AU - Magdaleno, Fernando

AU - Gröschl, Stefanie

AU - Loosen, Sven

AU - Ritz, Thomas

AU - Roderburg, Christoph

AU - Vucur, Michael

AU - Kristiansen, Glen

AU - Lammers, Twan

AU - Luedde, Tom

AU - Trebicka, Jonel

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Cirrhosis

KW - Fibrosis

KW - Inflammation

KW - Portal hypertension

U2 - 10.18632/oncotarget.26333

DO - 10.18632/oncotarget.26333

M3 - Journal article

C2 - 30546838

AN - SCOPUS:85056990209

VL - 9

SP - 36220

EP - 36237

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 90

ER -

Uschner FE, Schueller F, Nikolova I, Klein S, Schierwagen R, Magdaleno F et al. The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension. Oncotarget. 2018 nov 1;9(90):36220-36237. https://doi.org/10.18632/oncotarget.26333