TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.

ABSTRACT: Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-?B activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-?B activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox- and VP16-induced NF-?B activation and enhanced Dox- and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.

SUBMITTER: Fan Y 

PROVIDER: S-EPMC3778057 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature