Neuroblastoma is the most common extracranial solid
tumor of childhood and is responsible for over 15% of pediatric
cancer deaths.
Focal adhesion kinase (FAK) is a nonreceptor
tyrosine kinase that is important in many facets of
tumor development and progression.
Vascular endothelial growth factor receptor-3 (VEGFR-3), another
tyrosine kinase, has also been found to be important in the development of many human
tumors including
neuroblastoma. Recent reports have found that FAK and
VEGFR-3 interact, and we have previously shown that both of these
kinases interact in
neuroblastoma. We have hypothesized that interruption of the FAK-VEGFR-3 interaction would lead to decreased
neuroblastoma cell survival. In the current study, we examined the effects of a small molecule,
chloropyramine hydrochloride (C4), designed to disrupt the FAK-VEGFR-3 interaction, upon cellular attachment, migration, and survival in two human
neuroblastoma cell lines. We also utilized a murine xenograft model to study the impact of C4 upon
tumor growth. In these studies, we showed that disruption of the FAK-VEGFR-3 interaction led to decreased cellular attachment, migration, and survival in vitro. In addition, treatment of murine xenografts with
chloropyramine hydrochloride decreased
neuroblastoma xenograft growth. Further, this molecule acted synergistically with standard
chemotherapy to further decrease
neuroblastoma xenograft growth. The findings from this current study help to further our understanding of the regulation of
neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for
neuroblastoma and other solid
tumors of childhood.