Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition

Molecular Cancer

Research

Nicolas Charette¹  Isabelle Leclercq¹  Valérie Lannoy¹  Christine De Saeger¹  Yves Horsmans²  Peter Stärkel² 

[1] Laboratory of Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200, Brussels, Belgium;Laboratory of Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200, Brussels, Belgium;Department of Gastroenterology, Cliniques Universitaires Saint-Luc, 1200, Brussels, Belgium;

关键词: Epidermal Growth Factor;    HepG2 Cell;    mTOR Inhibition;    Huh7 Cell;    Hep3B Cell;   

DOI  :  10.1186/1476-4598-9-256

 received in 2010-04-27, accepted in 2010-09-22,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundDysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Salirasib is an S-prenyl-cysteine analog that has been shown to block ras and/or mTOR activation in several non hepatic tumor cell lines. We investigated in vitro the effect of salirasib on cell growth as well as its mechanism of action in human hepatoma cell lines (HepG2, Huh7, and Hep3B) and its in vivo effect in a subcutaneous xenograft model with HepG2 cells.ResultsSalirasib induced a time and dose dependent growth inhibition in hepatocarcinoma cells through inhibition of proliferation and partially through induction of apoptosis. A 50 percent reduction in cell growth was obtained in all three cell lines at a dose of 150 μM when they were cultured with serum. By contrast, salirasib was more potent at reducing cell growth after stimulation with EGF or IGF2 under serum-free conditions, with an IC50 ranging from 60 μM to 85 μM. The drug-induced anti-proliferative effect was associated with downregulation of cyclin A and to a lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction was related to a global pro-apoptotic balance with caspase 3 activation, cytochrome c release, death receptor upregulation, and a reduced mRNA expression of the apoptosis inhibitors cFLIP and survivin. These effects were associated with ras downregulation and mTOR inhibition, without reduction of ERK and Akt activation. In vivo, salirasib reduced tumour growth from day 5 onwards. After 12 days of treatment, mean tumor weight was diminished by 56 percent in the treated animals.ConclusionsOur results show for the first time that salirasib inhibits the growth of human hepatoma cell lines through inhibition of proliferation and induction of apoptosis, which is associated with ras and mTOR inhibition. The therapeutic potential of salirasib in human HCC was further confirmed in a subcutaneous xenograft model.

【 授权许可】

Unknown   
© Charette et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.