Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone
Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone
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DOI：
10.1016/j.ejca.2003.11.036
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发表时间：
2004-06-01
影响因子：
8.4
通讯作者：
Ilan, Y
中科院分区：
文献类型：
--
作者：
Nagler, A;Ohana, M;Ilan, Y
常山酮是一种广泛使用的生物碱抗球虫药，是胶原蛋白α 1（1）和基质金属蛋白酶2基因表达的有效抑制剂。常山酮还抑制细胞外基质沉积和成纤维细胞增殖。近年来发现它对膀胱癌和胶质瘤有较好的抑制作用。本研究旨在评估用常山酮治疗对小鼠肝细胞癌（HCC）生长的影响。向无胸腺Balb/c小鼠皮下注射10（7）个人肝癌细胞（Hep 3B），然后从第3天肿瘤接种前开始在饲料中给予卤夫酮（750 μ g/kg）进行治疗。对照组给予正常饮食。跟踪小鼠的存活率、肿瘤体积和血清甲胎蛋白（alphaFP）。通过评估肿瘤细胞生长，并通过测量干扰素-γ（IFN γ）和白细胞介素2（IL 2）的血清浓度，在体外确定了常山酮的抗肿瘤作用的机制。Halofuginone治疗在治疗的小鼠中诱导几乎完全的肿瘤抑制。常山酮处理组和对照组小鼠的死亡率分别为10%和50%（P < 0.001）。与对照组小鼠的364 mm（3）肿瘤相比，在治疗组小鼠中未观察到可见肿瘤。治疗组和对照组小鼠的血清alphaFP分别为0.1和212 ng/ml（P < 0.005）。常山酮在体外对肝癌细胞增殖有明显的抑制作用。在浓度为10（-8）M时，观察到肿瘤细胞生长的最大抑制率为64%。抗肿瘤作用通过IFN γ和IL 2的显著增加介导（治疗组和对照组分别为90对35和210对34 pg/ml，P < 0.005）。用常山酮治疗有效地抑制了小鼠中HCC的进展。这种作用可能与直接抗肿瘤作用和/或增强全身免疫应答有关。(C)2004爱思唯尔有限公司保留所有权利。
Halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of collagen alpha1 (1) and matrix metalloproteinase 2 gene expression. Halofuginone also suppresses extracellular matrix deposition and fibroblast proliferation. It was recently shown to be effective in suppression of bladder carcinoma and glioma. This study sought to evaluate the effect of treatment with halofuginone on growth of hepatocellular carcinoma (HCC) in mice. Athymic Balb/c mice were injected subcutaneously with 10(7) human hepatoma cells (Hep3B), followed by treatment with halofuginone administered in the diet (750 mug/kg) starting on day 3, before tumour innoculation. The control group was received a normal diet. Mice were followed for survival, tumour volume and serum alpha-feto-protein (alphaFP). The mechanism of the anti-tumour effect of halofuginone was determined in vitro by assessing tumour cell growth, and by measuring the serum concentrations of interferon-gamma (IFNgamma) and interleukin 2 (IL2). Halofuginone treatment induced almost complete tumour suppression in treated mice. Mortality rates were 10% and 50%, in halofuginone-treated and control mice, respectively (P < 0.001). No visible tumour was observed in treated mice, as compared with a 364 mm(3) tumour in control mice. Serum alphaFP were 0.1 and 212 ng/ml in treated and control mice, respectively (P < 0.005). Halofuginone significantly inhibited HCC proliferation in vitro. Maximal inhibition of 64% of tumour cell growth was observed at a concentration of 10(-8) M. The anti-tumour effect was mediated via a significant increase in IFNgamma and IL2 (90 vs. 35, and 210 vs. 34 pg/ml in treated and control groups, respectively, P < 0.005). Treatment with halofuginone effectively suppressed the progression of HCC in mice. This effect may be associated with a direct anti-tumour effect, and/or enhancement of a systemic immune response. (C) 2004 Elsevier Ltd. All rights reserved.