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Nordihydroguaiaretic acid inhibits insulin‐like growth factor signaling, growth, and survival in human neuroblastoma cells
Author(s) -
Meyer Gary E.,
Chesler Louis,
Liu Dandan,
Gable Karissa,
Maddux Betty A.,
Goldenberg David D.,
Youngren Jack F.,
Goldfine Ira D.,
Weiss William A.,
Matthay Katherine K.,
Rosenthal Stephen M.
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21373
Subject(s) - neuroblastoma , cancer research , nordihydroguaiaretic acid , insulin like growth factor , protein kinase b , mapk/erk pathway , apoptosis , biology , growth factor , endocrinology , medicine , signal transduction , microbiology and biotechnology , receptor , cell culture , biochemistry , genetics , arachidonic acid , enzyme
Abstract Neuroblastoma is a common pediatric malignancy that metastasizes to the liver, bone, and other organs. Children with metastatic disease have a less than 50% chance of survival with current treatments. Insulin‐like growth factors (IGFs) stimulate neuroblastoma growth, survival, and motility, and are expressed by neuroblastoma cells and the tissues they invade. Thus, therapies that disrupt the effects of IGFs on neuroblastoma tumorigenesis may slow disease progression. We show that NVP‐AEW541, a specific inhibitor of the IGF‐I receptor (IGF‐IR), potently inhibits neuroblastoma growth in vitro. Nordihydroguaiaretic acid (NDGA), a phenolic compound isolated from the creosote bush ( Larrea divaricata ), has anti‐tumor properties against a number of malignancies, has been shown to inhibit the phosphorylation and activation of the IGF‐IR in breast cancer cells, and is currently in Phase I trials for prostate cancer. In the present study in neuroblastoma, NDGA inhibits IGF‐I‐mediated activation of the IGF‐IR and disrupts activation of ERK and Akt signaling pathways induced by IGF‐I. NDGA inhibits growth of neuroblastoma cells and induces apoptosis at higher doses, causing IGF‐I‐resistant activation of caspase‐3 and a large increase in the fraction of sub‐G 0 cells. In addition, NDGA inhibits the growth of xenografted human neuroblastoma tumors in nude mice. These results indicate that NDGA may be useful in the treatment of neuroblastoma and may function in part via disruption of IGF‐IR signaling. J. Cell. Biochem. 102: 1529–1541, 2007. © 2007 Wiley‐Liss, Inc.