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

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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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Acknowledgments

We are very grateful to Dr. A. Davidoff and Dr. R. Seeger for providing the neuroblastoma cell lines described in this paper. We also thank Kristine Yang for editing our manuscript. This work was supported by the NIH/NINDS Grant 1R01NS072420-01 (to J.Y.). ** Cheng and Wei Jia are recipients of China Scholarship Council oversea training Grants.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Yihui Fan, ** Cheng, **n Xu, Yanling Zhao & Jianhua Yang

  2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Yihui Fan, ** Cheng, Sanjeev A. Vasudevan, Roma H. Patel, **n Xu, Yanling Zhao, Jed G. Nuchtern, Eugene S. Kim & Jianhua Yang

  3. Department of Microbiology, Peking University Health Science Center, Bei**g, 100191, China

    ** Cheng & Fengmin Lu

  4. Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA

    Sanjeev A. Vasudevan, Roma H. Patel, Jed G. Nuchtern & Eugene S. Kim

  5. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Li Liang, Wei Jia & Hong Zhang

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  1. Yihui Fan
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Correspondence to Jianhua Yang.

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Yihui Fan, ** Cheng and Sanjeev A. Vasudevan contributed equally to this work.

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Fan, Y., Cheng, J., Vasudevan, S.A. et al. TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy. Apoptosis 18, 1224–1234 (2013). https://doi.org/10.1007/s10495-013-0864-0

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