title: 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.
authors.affiliation: Division of Diabetes and Endocrine Research, San Francisco/Mt. Zion Medical Center, University of California, San Francisco, CA 94143-1616, USA. drjack@itsa.ucsf.edu
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: Karissa
authors.initials: K
authors.lastname: Gable
authors.forename: Cristina
authors.initials: C
authors.lastname: Penaranda
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Marianna
authors.initials: M
authors.lastname: Zavodovskaya
authors.forename: Margaret
authors.initials: M
authors.lastname: Lobo
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: John
authors.initials: J
authors.lastname: Kerner
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D010766:Phosphorylation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007334:Insulin-Like Growth Factor I; D009637:Masoprocol; D018719:Erb-b2 Receptor Tyrosine Kinases