Girnita Ada, Girnita Leonard, del Prete Fabrizio, Bartolazzi Armando, Larsson Olle, Axelson Magnus
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.
Cancer Res. 2004 Jan 1;64(1):236-42. doi: 10.1158/0008-5472.can-03-2522.
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-1R inhibitors have thus far been found. This is explained by the fact that IGF-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-1R 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 (LD(50) >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-1R as lead compounds in development of anticancer agents.
胰岛素样生长因子-1受体（IGF-1R）在恶性细胞的转化、生长和存活中起关键作用，已成为癌症治疗中一个普遍且有前景的靶点。然而，迄今为止尚未发现完全选择性的IGF-1R抑制剂。这是因为IGF-1R与胰岛素受体高度同源，对二者的共同抑制可能会引发糖尿病反应。这两种受体都是酪氨酸激酶，它们的ATP结合位点相同，这意味着ATP抑制剂无法区分它们。因此，目前的策略是在底物水平上鉴定干扰受体自身磷酸化的化合物。在本研究中，我们研究了环木脂素及相关分子对IGF-1R活性的影响。我们报告称，某些环木脂素是IGF-1R酪氨酸磷酸化的有效且选择性抑制剂。特别值得关注的是鬼臼苦素（PPP），它几乎无毒（在啮齿动物中的半数致死量>500 mg/kg）。PPP能有效阻断IGF-1R活性，降低pAkt以及细胞外信号调节激酶1和2的磷酸化水平（pErk1/2），诱导培养的IGF-1R阳性肿瘤细胞凋亡，并使异种移植和同种移植小鼠的肿瘤完全消退。在体外激酶试验中，PPP不影响胰岛素受体，也不与ATP竞争，这表明它可能在底物水平上抑制IGF-1R自身磷酸化。这也与我们关于环木脂素如何作用于IGF-1R激酶的分子模型一致。我们的结果为将对IGF-1R有抑制作用的PPP或相关化合物用作抗癌药物开发的先导化合物开辟了可能性。
