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

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

Apoptosis : an international journal on programmed cell death (2013-05-24)
Yihui Fan, Jin Cheng, Sanjeev A Vasudevan, Roma H Patel, Li Liang, Xin Xu, Yanling Zhao, Wei Jia, Fengmin Lu, Hong Zhang, Jed G Nuchtern, Eugene S Kim, Jianhua Yang
ABSTRACT

Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB 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-κB 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-κB 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.

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Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution