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.

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

“…These results show that ROS may perform essential functions for both the induction of airway inflammation and for the pathogenesis of asthmatic diseases. Previous studies have revealed that NDGA exerts pleiotropic effects capable of influencing a wide variety of cellular processes, including TGF-β-induced signal transduction, leukocyte chemotaxis, myoblast cell differentiation, cancer cell proliferation, and viral proliferation in infected cells (Goetzl et al, 1980;Gnabre et al, 1995;Lee et al, 2003;West et al, 2004;Ito et al, 2005;Youngren et al, 2005;Arasaki et al, 2007). However, its anti-inflammatory effects in allergic inflammation have been investigated to a lesser degree.…”

“…To that end, we utilized Nordihydroguaiaretic acid (NDGA), LOXs inhibitor. The results of previous studies have shown that NDGA exerts pleiotropic effects capable of influencing a broad variety of cellular processes, including growth factor-and TNF-induced signal transduction, leukocyte chemotaxis, myoblast cell differentiation, cancer cell proliferation, and viral proliferation in infected cells (Goetzl et al, 1980;Gnabre et al, 1995;Lee et al, 2003;West et al, 2004;Ito et al, 2005;Youngren et al, 2005;Arasaki et al, 2007). It can also induce the expression of NOS, regulate calcium channel activity, and inhibit the growth of β-amyloid protofibrils (Ramasamy et al, 1999;Huang et al, 2004;Moss et al, 2004).…”

Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF‐7 human breast cancer xenografts

“…Lignans may as well act via other non-hormone related mechanisms e.g. by inhibiting angiogenesis, 45 tyrosine kinases via IGF-1 receptor and c-erbB2/HER2/neu mediated pathways, 46 COX-2 expression 47 or DNA topoisomerase II. 48 Ovariectomized athymic mice with MCF-7 cells has limitations as an animal model to determine the effect of hormonally active compounds on postmenopausal breast cancer.…”

Drug delivery approaches for breast cancer

“…Inhibition of these RTKs helps in reduction of cell growth and drug development. 96 Several reports demonstrate the evidence for overexpression and hyperactivation of the IGF-IR in the early stages of breast cancer. [97][98][99] The negative expression of IGF-IR, using monoclonal antibodies, antisense IGF-IR, catechols, and transfection methods, Figure 3 Receptor-mediated drug delivery to metastatic breast cancer cells.…”