YM155 Inhibits Neuroblastoma Cell Migration and Survival <i>in Vitro</i> and Tumor Growth and Metastatic Burden in a Pre-Clinical Model

Abstract

Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both in vitro and in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15%-50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25%-70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma.

Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter

“…YM155 is an anticancer drug which causes DNA damage and survivin downregulation, and therefore was considered a promising treatment option in neuroblastoma 30 , 36 , 37 . However, neuroblastoma cells with high ABCB1 levels were intrinsically resistant to YM155 30 .…”