Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth
Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth
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DOI：
10.1158/0008-5472.can-03-2522
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发表时间：
2004-01-01
期刊：
影响因子：
11.2
通讯作者：
Axelson, M
中科院分区：
文献类型：
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作者：
Girnita, A;Girnita, L;Axelson, M
胰岛素样生长因子-1受体(IGF-1R)在肿瘤细胞的转化、生长和存活过程中起着关键作用，已成为治疗肿瘤的重要靶点。然而，到目前为止还没有发现完全选择性的IGF-IR抑制剂。这是因为LGF-1R与胰岛素受体高度同源，它的共同抑制可能会导致糖尿病反应。这两种受体都是酪氨酸激酶，它们的ATP结合部位是相同的，这意味着ATP抑制剂不能区分它们。因此，目前的策略是在底物水平上识别干扰受体自磷酸化的化合物。在这项研究中，我们研究了环木脂素及其相关分子对IGF-IR活性的影响。我们报道，某些环木脂素是IGF-1R酪氨酸磷酸化的有效和选择性抑制物。特别令人感兴趣的是鬼臼毒素(PPP)，它几乎无毒(啮齿类动物的LD50和GT；500毫克/公斤)。PPP可有效阻断IGF-1R活性，降低PACK和磷酸化细胞外信号调节蛋白1和2(pErk1/2)，诱导IGF-1R阳性肿瘤细胞的凋亡，并使异种和同种移植小鼠肿瘤完全消退。PPP不影响胰岛素受体，也不与ATP竞争，提示它可能在底物水平上抑制IGF-1R的自磷酸化。这也与我们的环木脂素如何作用于IGF-1R激酶的分子模型一致。我们的结果为PPP或具有抑制IGF-IR作用的相关化合物作为先导化合物开发抗癌药物提供了可能性。
The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of malignant cells, and has emerged as a general and promising target for cancer treatment. However, no fully selective IGF-IR inhibitors have thus far been found. This is explained by the fact that lGF-1R is highly homologous to the insulin receptor, coinhibition of which may cause diabetic response. The receptors are both tyrosine kinases, and their ATP binding sites are identical, implying that ATP inhibitors cannot discriminate between them. Therefore, the current strategy has been to identify compounds interfering with receptor autophosphorylation at the substrate level. In this study we investigated the effects of cyclolignans and related molecules on IGF-IR activity. We report that certain cyclolignans are potent and selective inhibitors of tyrosine phosphorylation of the IGF-1R. Of particular interest was picropodophyllin (PPP), which is almost nontoxic (LD50 >500 mg/kg in rodents). PPP efficiently blocked IGF-1R activity, reduced pAkt and phosphorylated extracellular signal regulated kinase 1 and 2 (pErk1/2), induced apoptosis in cultured IGF-1R-positive tumor cells, and caused complete tumor regression in xenografted and allografted mice. PPP did not affect the insulin receptor or compete with ATP in an in vitro kinase assay, suggesting that it may inhibit IGF-1R autophosphorylation at the substrate level. This is also in agreement with our molecular model of how the cyclolignans may act on the IGF-1R kinase. Our results open the possibility to use PPP or related compounds with inhibitory effects on IGF-IR as lead compounds in development of anticancer agents.