ReviewSorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes
Introduction
Hepatic fibrosis is a highly conserved response to liver injury that occurs in almost all types of liver disease [1]. The initial stage of liver fibrosis is commonly non-alcoholic fatty liver disease (NAFLD), which often found in the absence of significant alcohol consumption, viral infection, or autoimmune or drug-related liver injury [2]. NAFLD ranges from hepatic fat accumulation to non-alcoholic steatohepatitis (NASH). Approximately one third of the overall population suffer from NAFLD [3]. If NAFLD is not treated in time, it will progress to fibrosis [4]. Hepatic fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) that can cause hepatic dysfunction, can develop into cirrhosis. There is no curative treatment except liver transplantation [5], [6]. During this clinicopathological process, increased incidence of liver cancer also threatens cirrhotic patients [7]. Although anti-fibrotic activity has been confirmed in vivo and in vitro, few treatments have been thoroughly validated in the clinic or commercialized as a therapy for hepatic fibrosis. Thus, physicians and scientists are actively seeking curative interventions in the fibrotic process.
Recently, sorafenib has been reported to exert anti-fibrotic effects in liver fibrosis. Sorafenib is a multikinase inhibitor that inhibits both cell surface tyrosine kinase receptors and intracellular serine/threonine kinases in the Ras/MAPK cascade [8], [9], [10]. Sorafenib can inhibit receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGF-R), platelet-derived growth factor receptor (PDGF-R), c-kitproto-oncogene protein (c-KIT), FMS-like tyrosine kinase 3 (FLT-3), and RET; and downstream intracellular serine/threonine kinases, such as Raf-1, mutant B-Raf, and wild-type B-Raf [9], [10]. Sorafenib is an FDA approved molecular targeted drug for the treatment of advanced hepatocellular and renal cell carcinomas [11], [12], [13]. Inhibiting the pathways of RAF/MEK/ERK, decreasing tumor cell proliferation and angiogenesis, and increasing tumor cell apoptosis all contribute to the effects of sorafenib [14].
In addition to its established clinical benefits for patients with a broad range of tumor types, recent preclinical studies have demonstrated that sorafenib could be used to treat liver cirrhosis [15], [16], [17]. In rats, sorafenib ameliorated intrahepatic vascular resistance, and thus reduced portal hypertension, a major complication of fibrosis [15], [17]. Mejias et al. [15] first reported that sorafenib reduced intrahepatic fibrosis, inflammation, angiogenesis and portal hypertension in a cirrhotic rat model. Subsequent studies demonstrated that sorafenib also reduced the proliferation of hepatic stellate cells (HSC) and inhibited the synthesis of fibrogenesis-related proteins and the ECM [18], [19], [20].
Based on these findings in animal models, sorafenib could be considered a potential anti-fibrotic drug. Nevertheless, we do not have a clear understanding of the mechanisms of sorafenib in ameliorating hepatic fibrosis. In this review, we will highlight the potential molecular, cellular, microenvironmental mechanisms underlying the anti-fibrotic effects of sorafenib in fibrotic liver disease, and briefly discuss the potential of sorafenib for hepatic fibrogenesis and major complications in clinical treatments.
Section snippets
Liver cell types and potential molecular signaling pathways that link fibrosis
The progression of hepatic fibrosis is a complex process, involving parenchymal and non-parenchymal cells, including hepatocytes (HCs), liver sinusoidal endothelial cells (LECs), HSCs, and Kupffer cells [21]. These cells are important to the fibrotic process and complicated interplay amongst hepatic cell lineages occurs during fibrogenesis [22], [23]. Recently, attention has gradually shifted towards liver cells during regulation of the progression or regression of hepatic fibrosis [24].
Angiogenesis
Inflammatory mediators promote angiogenesis to maintain the inflammatory state in tissue by recruiting leucocytes and transporting nutrients and oxygen during the progression of fibrosis. Subsequently, the angiogenesis-related increased endothelial surface area creates an enormous capacity for inflammatory cytokines [55], [56], [57] .
Portal hypertension
Portal hypertension, the most important complication in patients with cirrhosis, is a serious and life-threatening disease, with few therapeutic options [15]. Portal hypertension in cirrhosis is initiated by an increased hepatic resistance to portal blood flow, caused by the distortion of liver vascular architecture and by an increased hepatic vascular tone. This is attributable to intrahepatic vasoconstriction secondary to an imbalance between decreased endogenous dilators [mainly nitric oxide
Adverse reactions
After approval by the European Union and the United States, sorafenib was identified to induce altered liver function by several trials, especially in patients with Child B/C cirrhosis [117], [118]. Moreover, the liver toxicity of sorafenib in the cirrhotic state emerged at low doses in several studies [117], [118], [119], [120]. Based on current results, for liver dysfunction or portal hypertension patients, dosage below the standard dose may be recommended. In addition, recent studies
Conclusions and perspectives
Liver fibrosis is a significant health problem resulting from the liver’s response to injury. Sorafenib has significant beneficial effects in inhibiting liver fibrosis. Currently, the mechanism of sorafenib’s effects on liver fibrosis remains ambiguous. Thus, a thorough understanding of the effect of sorafenib on hepatic fibrosis is important. Further studies are required before sorafenib can be applied in preclinical practice and therapy of liver fibrosis. The main issues of this potential
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgement
This work was supported by the Natural Science Foundation of Zhejiang Province [grant number LY15H030011].
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