Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

Abstract

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl4 for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti-inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α-smooth muscle actin, transforming growth factor (TGF)-β1 antibodies and platelet-derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl4 -induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF-β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)-1 and IL-6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF-β1 levels and decreasing expression of PDGFRβ.

Increasing the effectiveness of tyrosine kinase inhibitor (TKI) in combination with a statin in reducing liver fibrosis

“…The activation of HSCs results in the production of α‐SMA, expressing myofibroblasts, followed by the formation of type I collagen and ultimately fibrotic bundles . Therefore, dose‐dependent decrease in the expression of α‐SMA, CTGF, and PDGF was in line with the in vivo antifibrotic effects of these compounds, and also consistent with previous studies . Regarding the effect of the RhoA/ROCK pathway on the expression of CTGF, and PDGF, inhibition of this pathway can prevent the activation of HSCS, the expression of α‐SMA and the production of ECM.…”

“…Therefore, the inhibition of some RTKs pathway components such as VEGFR and PDGFR, and nRTKs such as c‐Abl, and c‐Src, along with rho‐kinase, led to the development of different treatments …”

Tyrosine kinase inhibitors: friends or foe in treatment of hepatic fibrosis?

“…It was found that sorafenib could inhibit proliferation of HSCs by downregulating expression of cyclins and cyclin dependent kinases (CDKs) and prevent ERK, Akt and 70-kDa ribosomal S6 kinase (p70S6K) from phosphorylation [11, 12], [13]. In addition, several other TKIs, such as imatinib [14], vatalanib [15–17], nilotinib [18–22], erlotinib [23, 24] and brivanib [25, 26], were also found to prevent HSC activation, resulting in less collagen deposition.…”

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis

“…Several studies showed that Nilotinib can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin-(IL-) 1 and IL-6 [6][7][8][9]. In an earlier study, we compared Nilotinib, Imatinib, and silymarin in their effect as antifibrotic agents [4]; we found that Nilotinib is better than silymarin and less toxic than Imatinib, and also, we found that Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases [7].…”