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

  • Jack F. Youngren
  • Karissa Gable
  • Cristina Penaranda
  • Betty A. Maddux
  • Marianna Zavodovskaya
  • Margaret Lobo
  • Michael Campbell
  • John Kerner
  • Ira D. Goldfine
Report

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.

Key words

MCF-7 cells proliferation small molecule inhibitor syngeneic mouse model tyrosine kinase 

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Copyright information

© Springer 2005

Authors and Affiliations

  • Jack F. Youngren
    • 1
  • Karissa Gable
    • 1
  • Cristina Penaranda
    • 1
  • Betty A. Maddux
    • 1
  • Marianna Zavodovskaya
    • 1
  • Margaret Lobo
    • 2
  • Michael Campbell
    • 2
  • John Kerner
    • 3
  • Ira D. Goldfine
    • 1
  1. 1.Division of Diabetes and Endocrine Research, San Francisco/Mt. Zion Medical CenterUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Surgery, San Francisco/Mt. Zion Medical CenterUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of Medicine, Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of CaliforniaSan FranciscoUSA

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