Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppresses growth in breast cancer cells
Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppresses growth in breast cancer cells
复制标题
DOI：
10.1007/s10549-005-6939-z
复制
发表时间：
2005-11-01
影响因子：
3.8
通讯作者：
Goldfine, ID
中科院分区：
文献类型：
--
作者：
Youngren, JF;Gable, K;Goldfine, ID
北二氢愈创木酸（NDGA）是一种从木酚灌木中分离得到的酚类化合物，在体内和体外均具有抗癌活性。我们现在可以将乳腺癌细胞中的某些抗癌特性归因于NDGA直接抑制两种受体酪氨酸激酶（rtk），胰岛素样生长因子受体（IGF-1R）和c-erbB2/HER2/neu （HER2/neu）受体功能的能力。在MCF-7人乳腺癌细胞中，低微摩尔浓度的NDGA抑制了IGF-1R的激活，以及Akt/PKB丝氨酸激酶和促凋亡蛋白BAD的下游磷酸化。在小鼠MCNeuA细胞中，NDGA也抑制了HER2/neu不依赖配体的磷酸化。为了研究细胞中的这种抑制作用是否由于直接作用于这些受体，我们研究了igf -1刺激分离的IGF-1R的酪氨酸激酶活性，NDGA在10 μ M或更小的浓度下抑制了IGF-1R。NDGA在相似浓度下也能有效抑制分离的HER2/neu受体的自磷酸化。此外，NDGA抑制培养的乳腺癌细胞IGF-1特异性生长，IC50约为30 μ M. NDGA处理（每周3次腹腔注射）也降低了MCNeuA细胞中IGF-1R和HER2/neu受体的活性。RTK活性的抑制与MCNeuA细胞体内生长速率的降低有关。这些研究表明NDGA的抗乳腺癌特性与抑制两种重要的rtk有关。因此，这类药物可能为这种疾病的潜在治疗提供新的见解。
Nordihydroguaiaretic acid (NDGA) is a phenolic compound isolated from the creosote bush Larrea divaricatta that has anti-cancer activities both in vitro and in vivo. We can now attribute certain of these anti-cancer properties in breast cancer cells to the ability of NDGA to directly inhibit the function of two receptor tyrosine kinases (RTKs), the insulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/neu (HER2/neu) receptor. In MCF-7 human breast cancer cells, low micromolar concentrations of NDGA inhibited activation of the IGF-1R, and downstream phosphorylation of both the Akt/PKB serine kinase and the pro-apoptotic protein BAD. In mouse MCNeuA cells, NDGA also inhibited ligand independent phosphorylation of HER2/neu. To study whether this inhibitory effect in cells was due to a direct action on these receptors, we studied the IGF-1-stimulated tyrosine kinase activity of isolated IGF-1R, which was inhibited by NDGA at 10 mu M or less. NDGA was also effective at inhibiting autophosphorylation of the isolated HER2/neu receptor at similar concentrations. In addition, NDGA inhibited IGF-1 specific growth of cultured breast cancer cells with an IC50 of approximately 30 mu M. NDGA treatment (intraperitoneal injection 3 times per week) also decreased the activity of the IGF-1R and the HER2/neu receptor in MCNeuA cells implanted into mice. This inhibition of RTK activity was associated with decreased growth rates of MCNeuA cells in vivo. These studies indicate that the anti-breast cancer properties of NDGA are related to the inhibition of two important RTKs. Agents of this class may therefore provide new insights into potential therapies for this disease.