title: The effect of Ras inhibition on the proliferation, apoptosis and matrix metalloproteases activity in rat hepatic stellate cells.
abstract: In vivo inhibition of Ras by its antagonist farnesylthiosalicylic acid (FTS) prevents and reverses liver fibrosis in a rat model. In this study we showed the in vitro effects of Ras inhibition in a rat hepatic stellate cell line, HSC-T6. The IC(50) of FTS that inhibited PDGF-induced proliferation was 15 microM. FTS, by itself or in combination with PDGF, induced a three- to fivefold increase in the number of apoptotic stellate cells but did not induce apoptosis in cells cultured with TGFbeta1. We observed increased activity of MMP-9 and MMP-2 induced by FTS in combination with PDGF or TGFbeta. FTS, alone or in the presence of PDGF and TGFbeta, reduced collagen I mRNA expression. In conclusion, the in vivo amelioration of liver fibrosis by FTS may be explained by its ability to inhibit hepatic stellate cell proliferation, induce apoptosis and MMP-2 and MMP-9 activity, and decrease collagen I expression.
authors.affiliation: Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, Israel. isab@tasmc.health.gov.il
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
authors.forename: Dan
authors.initials: D
authors.lastname: Bar-Zohar
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Ran
authors.initials: R
authors.lastname: Oren
authors.forename: Shimon
authors.initials: S
authors.lastname: Reif
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D024042:Collagen Type I; D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D020782:Matrix Metalloproteinases; D018631:ras Proteins