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

Abstract
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.
AuthorsJack F Youngren, Karissa Gable, Cristina Penaranda, Betty A Maddux, Marianna Zavodovskaya, Margaret Lobo, Michael Campbell, John Kerner, Ira D Goldfine
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 94 Issue 1 Pg. 37-46 (Nov 2005) ISSN: 0167-6806 [Print] Netherlands
PMID16142439 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Insulin-Like Growth Factor I
  • Masoprocol
  • Receptor, ErbB-2
Topics
  • Analysis of Variance
  • Animals
  • Apoptosis (drug effects)
  • Breast Neoplasms (physiopathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Female
  • Insulin-Like Growth Factor I (antagonists & inhibitors)
  • Masoprocol (pharmacology)
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental
  • Phosphorylation (drug effects)
  • Receptor, ErbB-2 (antagonists & inhibitors)
  • Signal Transduction (drug effects)

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