Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HEF12-overexpressing human breast cancer cells
Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HEF12-overexpressing human breast cancer cells
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DOI：
10.1002/jcb.21435
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发表时间：
2008-02-01
影响因子：
4
通讯作者：
Goldfine, Ira D.
中科院分区：
文献类型：
--
作者：
Zavodovskaya, Marianna;Campbel, Michael J.;Goldfine, Ira D.
我们已经报道了去甲二氢愈创木酸（NDGA）抑制乳腺癌细胞中IGF-1受体（IGF-1 R）和HER 2受体的酪氨酸激酶活性。在此，我们研究了NDGA对过表达HER 2的雌激素受体（ER）阳性MCF-7细胞（MCF-7/HER 2 -18）生长的影响。这些细胞是HER 2驱动的、ER阳性的、他莫昔芬抗性乳腺癌的体外模型。NDGA在抑制亲本MCF-7和MCF-7/HER 2 -18细胞的生长方面同样有效。两种细胞系的半数最大效应在10-15 μ M范围内。NDGA的生长抑制作用与细胞周期的S期阻滞和诱导凋亡有关。NDGA抑制这些乳腺癌细胞中的IGF-1 R和HER 2激酶活性。相比之下，吉非替尼（一种表皮生长因子受体抑制剂，但不是IGF-1 R抑制剂）在MCF-7/HER 2 -18细胞中比在亲本MCF-7细胞中更有效，IGF结合蛋白-3（IGFBP-3）对MCF-7细胞的作用比MCF-7/HER 2 -18更有效。已知MCF-7/HER 2 -18细胞对雌激素受体抑制剂他莫昔芬的作用具有抗性。有趣的是，NDGA不仅单独抑制MCF-7/HER 2 -18的生长，而且当与他莫昔芬组合时，还表现出累加的生长抑制作用。这些研究表明，NDGA可能对HER 2阳性、他莫昔芬耐药的人类乳腺癌具有治疗益处。
We have reported that nordihydroguaiaretic acid (NDGA) inhibits the tyrosine kinase activities of the IGF-1 receptor(IGF-1R) and the HER2 receptor in breast cancer cells. Herein, we studied the effects of NDGA on the growth of estrogen receptor(ER) positive MCF-7 cells engineered to overexpress HER2 (MCF-7/HER2-18). These cells are an in vitro model of HER2-driven, ER positive, tamoxifen resistant breast cancer. NDGA was equally effective at inhibiting the growth of both parental MCF-7 and MCF-7/HER2-18 cells. Half maximal effects for both cell lines were in the 10-15 mu M range. The growth inhibitory effects of NDGA were associated with an S phase arrest in the cell cycle and the induction of apoptosis. NDGA inhibited both IGF-1R and HER2 kinase activities in these breast cancer cells. In contrast, Gefitinib, an epidermal growth factor receptor inhibitor but not an IGF-1R inhibitor, was more effective in MCF-7/HER2-18 cells than in the parental MCF-7 cells and IGF binding protein-3 (IGFBP-3) was more effective against MCF-7 cells compared to MCF-7/HER2-18. MCF-7/HER2-18 cells are known to be resistant to the effects of the estrogen receptor inhibitor, tamoxifen. Interestingly, NDGA not only inhibited the growth of MCF-7/HER2-18 on its own, but it also demonstrated additive growth inhibitory effects when combined with tamoxifen. These studies suggest that NDGA may have therapeutic benefits in HER2-positive, tamoxifen resistant, breast cancers in humans.