Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HEF12-overexpressing human breast cancer cells

被引:37
|
作者
Zavodovskaya, Marianna [1 ]
Campbel, Michael J. [2 ]
Maddux, Betty A. [1 ]
Shiry, Laura [3 ]
Allan, Geoffrey [3 ]
Hodges, Leslie [4 ]
Kushner, Peter [4 ]
Kerner, John A. [5 ]
Youngren, Jack F. [1 ]
Goldfine, Ira D. [1 ]
机构
[1] Univ Calif San Francisco, Mt Zion Med Ctr, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Mt Zion Med Ctr, Dept Surg, San Francisco, CA 94143 USA
[3] Insmed Inc, Glen Allen, VA USA
[4] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Dept Med, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA
关键词
NDGA; receptor tyrosine kinase; HER2; IGF-1R; breast cancer;
D O I
10.1002/jcb.21435
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:624 / 635
页数:12
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