title: Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HER2-overexpressing human breast cancer cells.
abstract: We have reported that nordihydroguaiaretic acid (NDGA) inhibits the tyrosine kinase activities of the IGF-1 receptor (IGF-1R) and the HER2 receptor in breast cancer cells. Herein, we studied the effects of NDGA on the growth of estrogen receptor (ER) positive MCF-7 cells engineered to overexpress HER2 (MCF-7/HER2-18). These cells are an in vitro model of HER2-driven, ER positive, tamoxifen resistant breast cancer. NDGA was equally effective at inhibiting the growth of both parental MCF-7 and MCF-7/HER2-18 cells. Half maximal effects for both cell lines were in the 10-15 microM range. The growth inhibitory effects of NDGA were associated with an S phase arrest in the cell cycle and the induction of apoptosis. NDGA inhibited both IGF-1R and HER2 kinase activities in these breast cancer cells. In contrast, Gefitinib, an epidermal growth factor receptor inhibitor but not an IGF-1R inhibitor, was more effective in MCF-7/HER2-18 cells than in the parental MCF-7 cells and IGF binding protein-3 (IGFBP-3) was more effective against MCF-7 cells compared to MCF-7/HER2-18. MCF-7/HER2-18 cells are known to be resistant to the effects of the estrogen receptor inhibitor, tamoxifen. Interestingly, NDGA not only inhibited the growth of MCF-7/HER2-18 on its own, but it also demonstrated additive growth inhibitory effects when combined with tamoxifen. These studies suggest that NDGA may have therapeutic benefits in HER2-positive, tamoxifen resistant, breast cancers in humans.
authors.affiliation: Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, San Francisco, California, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Zavodovskaya
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Laura
authors.initials: L
authors.lastname: Shiry
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Allan
authors.forename: Leslie
authors.initials: L
authors.lastname: Hodges
authors.forename: Peter
authors.initials: P
authors.lastname: Kushner
authors.forename: John A
authors.initials: JA
authors.lastname: Kerner
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000077156:Gefitinib; D018972:Insulin-Like Growth Factor Binding Protein 3; D009637:Masoprocol; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C508053:ERBB2 protein, human