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-G0 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.