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
Department of Pediatrics, University of California, San Francisco, California 94143, USA.
J Cell Biochem. 2007 Dec 15;102(6):1529-41. doi: 10.1002/jcb.21373.
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.
神经母细胞瘤是一种常见的儿科恶性肿瘤，可转移至肝脏、骨骼和其他器官。患有转移性疾病的儿童采用当前治疗方法的生存率不到50%。胰岛素样生长因子（IGFs）可刺激神经母细胞瘤的生长、存活和迁移，并且由神经母细胞瘤细胞及其侵袭的组织表达。因此，破坏IGFs对神经母细胞瘤肿瘤发生影响的疗法可能会减缓疾病进展。我们发现，IGF-I受体（IGF-IR）的特异性抑制剂NVP-AEW541在体外能有效抑制神经母细胞瘤的生长。去甲二氢愈创木酸（NDGA）是从杂酚油灌木（Larrea divaricata）中分离出的一种酚类化合物，对多种恶性肿瘤具有抗肿瘤特性，已被证明可抑制乳腺癌细胞中IGF-IR的磷酸化和激活，目前正处于前列腺癌的I期试验阶段。在目前针对神经母细胞瘤的研究中，NDGA可抑制IGF-I介导的IGF-IR激活，并破坏由IGF-I诱导的ERK和Akt信号通路的激活。NDGA可抑制神经母细胞瘤细胞的生长，并在较高剂量时诱导细胞凋亡，导致caspase-3的IGF-I抗性激活以及亚G0期细胞比例大幅增加。此外，NDGA可抑制裸鼠体内移植的人神经母细胞瘤肿瘤的生长。这些结果表明，NDGA可能对神经母细胞瘤的治疗有用，并且可能部分通过破坏IGF-IR信号发挥作用。
