Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats #

Abstract

Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor ␤ (PDGFR-␤), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. Conclusion: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension. (HEPATOLOGY 2009;49:1245-1256 See Editorial on Page 1066 P ortal hypertension is the most important complication that develops in patients with cirrhosis of the liver and remains a leading cause of morbidity and mortality worldwide. 1 The portal hypertensive syndrome is characterized by a pathological increase in portal pressure and by the development of hyperdynamic splanchnic circulation, with an increase in blood flow in splanchnic organs draining into the portal vein and a subsequent elevation in portal venous inflow. Such increased portal venous inflow is a significant factor maintaining and worsening portal pressure elevation and determining the formation of ascites. Another characteristic feature of portal hypertension is the formation of an extensive network of portosystemic collateral vessels; these include gastroesophageal varices, which are prone to rupture that can cause massive, life-threatening gastroesophageal bleeding. In addition, collateral vessels result in shunting of portal blood into the systemic circulation ...

Letter: sorafenib in portal hypertension – authors' reply

“…However, the findings extend nicely the principle observation from animal experiments 4 to the clinical setting, with about one-third of treated individuals showing an improvement in portal hypertension with sorafenib, an effect of about the same magnitude as can be expected from the treatment of portal hypertensive patients with nonselective b-blockers like propranolol or nadolol. 5 We agree with Procopet et al that for studying the antihypertensive effects of sorafenib, patients with HCC are not an ideal patient population, but for lack of other options to test the drug so far, both of our groups did resort to this group of patients to perform a proofof-principle study on the haemodynamic effects of sorafenib in humans.…”

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

“…Sorafenib may have various effects on different cell types. Mejias et al first reported sorafenib ameliorated portal hypertension, intrahepatic fibrosis, inflammation, and angiogenesis in a cirrhotic rat model (19). Subsequent studies demonstrated sorafenib might reduce HSC proliferation, and inhibit the synthesis of fibrogenesis-related proteins and extracellular matrix (7,20,21).…”

Sorafenib inhibits transforming growth factor β1-Mediated Epithelial-Mesenchymal Transition and apoptosis in mouse hepatocytes

“…16,17,36 However, very little is known regarding the mechanism underlying these effects. Our results largely extend these studies by identifying the mechanism for modulation of TGF-b signaling by sorafenib and highlighting the biological function of sorafenib in TGF-b-induced EMT and apoptosis in vitro.…”

“…14,15 In addition to its established clinical benefits for patients with a broad range of tumor types, recent studies in rats have demonstrated that sorafenib has potential utility in the treatment of portal hypertension and cirrhosis. 16,17 However, a detailed understanding of the underlying molecular mechanism remains elusive. In the current study we identified a new function for sorafenib as an effective inhibitor of TGF-b signaling.…”