Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition.
Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition.
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DOI：
10.1186/1476-4598-9-256
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发表时间：
2010-09-22
期刊：
影响因子：
37.3
通讯作者：
Stärkel P
中科院分区：
文献类型：
--
作者：
Charette N;De Saeger C;Lannoy V;Horsmans Y;Leclercq I;Stärkel P
表皮生长因子和胰岛素样生长因子信号传导失调在人肝细胞癌 (HCC) 中发挥重要作用，导致其下游靶点、ras/raf/细胞外信号调节激酶 (ERK) 和磷酸肌醇 3-激酶 (PI3K)/Akt/哺乳动物雷帕霉素靶点 (mTOR) 通路频繁激活。 Salirasib 是一种 S-异戊二烯基半胱氨酸类似物，已被证明可以在多种非肝肿瘤细胞系中阻断 ras 和/或 mTOR 激活。我们在体外研究了 salirasib 对细胞生长的影响及其在人肝癌细胞系（HepG2、Huh7 和 Hep3B）中的作用机制，以及在 HepG2 细胞皮下异种移植模型中的体内作用。 Salirasib 通过抑制增殖并部分通过诱导细胞凋亡来诱导肝癌细胞的时间和剂量依赖性生长抑制。当所有三种细胞系与血清一起培养时，剂量为 150 μM 时，细胞生长均减少 50%。相比之下，在无血清条件下用 EGF 或 IGF2 刺激后，salirasib 在减少细胞生长方面更有效，IC50 范围为 60 μM 至 85 μM。药物诱导的抗增殖作用与细胞周期蛋白 A 的下调和细胞周期蛋白 D1 的较小程度的下调以及 p21 和 p27 的上调有关。细胞凋亡诱导与 caspase 3 激活、细胞色素 c 释放、死亡受体上调以及细胞凋亡抑制剂 cFLIP 和生存素 mRNA 表达减少等全局促细胞凋亡平衡相关。这些效应与 ras 下调和 mTOR 抑制相关，但不减少 ERK 和 Akt 激活。在体内，salirasib 从第 5 天起就减少了肿瘤的生长。治疗 12 天后，接受治疗的动物的平均肿瘤重量减少了 56%。我们的结果首次表明，salirasib 通过抑制增殖和诱导细胞凋亡来抑制人肝癌细胞系的生长，这与 ras 和 mTOR 抑制有关。 salirasib 在人类 HCC 中的治疗潜力在皮下异种移植模型中得到进一步证实。
Dysregulation 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. Salirasib 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. Our 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.
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影响因子：
13.5
作者：
Gonzalez-Rodriguez, Agueda;Alba, Javier;Zimmerman, Valeri;Kozma, Sara C.;Valverde, Angela M.
通讯作者：
Valverde, Angela M.
影响因子：
11.5
作者：
Chitnis, Meenali M.;Yuen, John S. P.;Macaulay, Valentine M.
通讯作者：
Macaulay, Valentine M.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
20.3
作者：
Decker, T;Hipp, S;Peschel, C
通讯作者：
Peschel, C
影响因子：
4.8
作者：
MAROM, M;HAKLAI, R;KLOOG, Y
通讯作者：
KLOOG, Y