The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats
| Autor: | Isabelle Leclercq, Peter Stärkel, Ivan Borbath, Jorge Abarca, C. De Saeger, Yves Horsmans, N. Charette, T. Schneider-Merck |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Programmed cell death medicine.medical_specialty Carcinoma Hepatocellular Cyclin D Blotting Western Antineoplastic Agents Apoptosis Caspase 3 Fas ligand Internal medicine medicine Membrane activity Animals Diethylnitrosamine Rats Wistar Ras Inhibitor Caspase 8 biology Liver Neoplasms Farnesol Immunohistochemistry Salicylates Rats Gene Expression Regulation Neoplastic Genes ras Endocrinology medicine.anatomical_structure Oncology Hepatocyte Models Animal Hepatocytes biology.protein Cancer research Biomarkers |
| Zdroj: | European Journal of Cancer. 45:2050-2060 |
| ISSN: | 0959-8049 |
| DOI: | 10.1016/j.ejca.2009.04.014 |
| Popis: | BACKGROUND: Aberrant activation of oncogenes, such as Ras, likely contributes to the development of hepatocarcinoma (HCC). AIMS/METHODS: 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. |
| Databáze: | OpenAIRE |
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