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.