Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Abstract

Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.

The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer

“…Additionally, animals treated with sorafenib showed HSC phenotype amelioration, resulting in PP reduction [188]. In accordance with this, it has been demonstrated that sorafenib ameliorates the HSC phenotype by decreasing ECM deposition and the expression of fibrinogenic molecules in liver fibrosis [189].…”

“…Tyrosine kinase receptor inhibitors were suggested as a therapeutic option for angiogenesis occurring in advanced CLD [188,189]. In this context, rats with intrahepatic PH treated with sorafenib showed the inhibition of endothelial angiogenic and proliferative markers such as VEGFR-2 and PDGFRβ through the suppression of the Raf/MEK/ERK signalling pathway.…”

Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management

“…Sunitinib is an indolin-2-one structural analog that is taken orally and inhibits various RTKs including VEGFR1/2/3, PDGFR, FGFR, and c-Kit [ 128 ]. Sunitinib demonstrated potent anti-tumor and anti-angiogenesis effects in a variety of cancer types in clinical trials.…”