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Nordihydroguaiaretic Acid (NDGA) Inhibits the IGF-1 and c-erbB2/HER2/neu Receptors and Suppresses Growth in Breast Cancer Cells

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Summary

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 μM 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 μM. 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.

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Authors and Affiliations

  1. Division of Diabetes and Endocrine Research, San Francisco/Mt. Zion Medical Center, University of California, San Francisco, CA, USA

    Jack F. Youngren, Karissa Gable, Cristina Penaranda, Betty A. Maddux, Marianna Zavodovskaya & Ira D. Goldfine

  2. Department of Surgery, San Francisco/Mt. Zion Medical Center, University of California, San Francisco, CA, USA

    Margaret Lobo & Michael Campbell

  3. Department of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, Box 0856, San Francisco, CA, USA

    John Kerner

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  1. Jack F. Youngren
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Correspondence to Jack F. Youngren.

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Youngren, J.F., Gable, K., Penaranda, C. et al. Nordihydroguaiaretic Acid (NDGA) Inhibits the IGF-1 and c-erbB2/HER2/neu Receptors and Suppresses Growth in Breast Cancer Cells. Breast Cancer Res Treat 94, 37–46 (2005). https://doi.org/10.1007/s10549-005-6939-z

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