The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats.
BACKGROUND
Aberrant activation of oncogenes, such as Ras, likely contributes to the development of hepatocarcinoma (HCC).


OBJECTIVE
We evaluated in vivo the effect of intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) on Ras activation and the development of preneoplastic liver lesions in rats receiving weekly diethylnitrosamine (DEN) injections for 16weeks. Western blotting, quantitative PCR, immunohistochemistry, Tunel and caspase activity assays were used.


RESULTS
FTS prevents liver nodule formation and reduces foci expressing the tumour marker GSTp. FTS abrogates DEN-induced Ras membrane activity, increases Tunel positive cells in transformed, GSTp-expressing hepatocytes, up-regulates caspase 3 and 8 activity, induces Fas, Fas ligand and JNK phosphorylation that occurs independently of TNFalpha and Trail. Cytochrome C release, Bax, Bcl2, Bcl-xl, Ki67 and nuclear cyclin D expression is not affected by FTS.


CONCLUSIONS
FTS inhibits Ras activation and prevents preneoplastic liver nodule development by inducing apoptosis in transformed hepatocytes through activation of the Fas/Fas ligand system. FTS might be new molecule for HCC treatment.
Laboratory of Gastroenterology, St University Hospital, Université Catholique de Louvain, 1200 Brussels, Belgium.
T
T
Schneider-Merck
I
I
Borbath
N
N
Charette
C
C
De Saeger
J
J
Abarca
I
I
Leclercq
Y
Y
Horsmans
P
P
Stärkel
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control; D053148:Caspase 3 / Q000032:analysis; D053181:Caspase 8 / Q000032:analysis; D004052:Diethylnitrosamine; D005204:Farnesol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control; D008297:Male; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015415:Biomarkers; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D004052:Diethylnitrosamine; D005204:Farnesol; D053148:Caspase 3; D053181:Caspase 8