Imatinib mesylate (STI571: Gleevec) attenuates liver fibrosis development in rats.

It is now widely recognized that the activated hepatic stellate cells (HSC) play a pivotal role in the liver fibrosis development. A platelet-derived growth factor (PDGF) is the most potent mitogen for the HSC. The aim of this study was to examine the effect of imatinib mesylate (STI571; Gleevec), which is a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor, on the experimental liver fibrosis development. The rat model of pig serum-induced hepatic fibrosis was used to assess the effect of daily oral administration of STI571 on the indices of fibrosis. STI571 markedly attenuated the liver fibrosis development, hepatic hydroxyproline and serum fibrosis markers. The number of alpha-smooth muscle actin (alpha- SMA)-positive cells, and the mRNA expressions of alpha2-(I)-procollagen, tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor-beta (TGF-beta) were also significantly suppressed by STI571 treatment. Our in vitro study showed that STI571 markedly attenuated the PDGF-BB-induced proliferation, migration, and alpha-SMA, alpha2-(I)-procollagen mRNA of the activated HSC in a dose-dependent manner. STI571 also significantly attenuated the PDGF-BB-induced phosphorylation of PDGFR-beta, MEK1/2, and Akt in the activated HSC. Because STI571 is widely used in the clinical practice, this drug may provide an effective new strategy for anti-fibrosis therapy.