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

Abstract

It has been shown that both nilotinib as a tyrosine kinase inhibitor, and atorvastatin as a rho-kinase inhibitor, have antifibrotic effects. Therefore, considering the relationship between these two pathways, this study aimed to investigate the effects of their co-treatment against hepatic stellate cells (HSCs) activation and liver fibrosis. For this purpose, the activation of HSCs coincided with these therapies. Also, liver fibrosis by carbon tetrachloride (CCl4) was induced in male Wistar rats and treated simultaneously with these compounds. The expression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), Ras homolog gene family, and member A (RhoA)/Rho-associated protein kinase (ROCK) in HSCs were measured. The expression of transforming growth factor beta-1 (TGF-beta 1), its receptor (T beta RII), CTGF, and platelets derived growth factor (PDGF), in the livers, were also investigated, all by real-time PCR and western blot analysis. Also, histopathologic and immunohistochemical evaluations were performed to evaluate changes in liver fibrosis during treatment. The results indicated the down-regulation of RhoA/ROCK, CTGF, and alpha-SMA, and inhibition of the HSCs activation toward myofibroblasts. The results also showed that the combined use of atorvastatin and nilotinib has significantly higher inhibitory effects. The antifibrotic effects of atorvastatin and nilotinib co-administration were also observed by histopathologic and immunohistochemical observations, and inhibiting the expression of TGF-beta 1, T beta RII, CTGF, and PDGF. Taken together, this study revealed that co-administration of nilotinib-atorvastatin has novel antifibrotic effects, by inhibiting RhoA/ROCK, and CTGF pathway. Therefore, the importance of the common pathway of RhoA/ROCK and CTGF, in reducing fibrosis may almost be concluded.