Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppresses growth in breast cancer cells

• Published in: Breast cancer research and treatment 2005-11, Vol.94 (1), p.37-46
• Main Authors: YOUNGREN, Jack F, GABLE, Karissa, PENARANDA, Cristina, MADDUX, Betty A, ZAVODOVSKAYA, Marianna, LOBO, Margaret, CAMPBELL, Michael, KERNER, John, GOLDFINE, Ira D
• Format: Article
• Language: English
• Subjects: Acids; Analysis of Variance; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Breast cancer; Breast Neoplasms - physiopathology; Cancer research; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Female; Gynecology. Andrology. Obstetrics; Insulin-Like Growth Factor I - antagonists & inhibitors; Mammary gland diseases; Masoprocol - pharmacology; Medical sciences; Medical treatment; Mice; Mice, Transgenic; Neoplasms, Experimental; Oncology; Pharmacology. Drug treatments; Phosphorylation - drug effects; Proteins; Receptor, ErbB-2 - antagonists & inhibitors; Signal Transduction - drug effects; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-005-6939-z

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 muM 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 muM. 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.