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Artemisitene suppresses tumorigenesis by inducing DNA damage through deregulating c-Myc-topoisomerase pathway

Oncogene volume 37, pages 5079–5087 (2018)Cite this article

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Abstract

Cancer chemotherapeutic agents such as doxorubicin are DNA damage inducers that also kill normal cells, making them highly toxic to cancer patients. To improve the efficacy and safety of chemotherapy, it is important to develop new chemotherapeutic agents that selectively kill cancer cells. Here we demonstrate that artemisitene (ATT), a natural derivative of the antimalarial drug artemisinin, selectively induces DNA double-stranded breaks (DSBs) and apoptosis in various human cancer cells by suppressing the expression of topoisomerases in human cancer cells. ATT effectively kills human cancer cells without apparent cytotoxicity on normal human cells or mouse liver and kidney. We discovered that c-Myc induces the expression of topoisomerases to prevent accumulation of DNA damage in human cancer cells. ATT selectively destabilizes c-Myc in human cancer cells by promoting the ubiquitination of c-Myc through the specific induction of the c-Myc E3 ligase NEDD4. Therefore, ATT represents a promising new chemotherapeutic drug candidate that can eliminate human cancer cells with minimized cytotoxic effects on normal cells.

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Acknowledgements

Wenjuan Li was supported by a fellowship from Postdoctoral Science Foundation of China (2015M582371). This study was supported by NSFC (nos. 81430032, U1601222, 81502595), Guangdong Provincial Key Laboratory of Cancer Immunotherapy, Guangzhou Key Laboratory of Tumor Immunology Research, Guangdong Provincial Key Special Science and Technology Project (2015B020225004), Guangdong NSF Major basic research developmental project, and grants from California Institute for Regenerative Medicine.

Author contributions

J.C., W.L., K.C., K.J., S.X. performed experiments. J.C. and Y.X. designed the study and analyzed the data. Y.X. provided the administrative support. J.C., W.L., K.C., and Y.X. wrote the first draft of the manuscript and all authors participated in the revision of the manuscript.

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Jian Chen, Kaiyuan Ji, Shuxiang Xu & Yang Xu

  2. Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510632, China

    Wenjuan Li, Ke Cui & Yang Xu

  3. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0322, USA

    Yang Xu

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Correspondence to Yang Xu.

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Chen, J., Li, W., Cui, K. et al. Artemisitene suppresses tumorigenesis by inducing DNA damage through deregulating c-Myc-topoisomerase pathway. Oncogene 37, 5079–5087 (2018). https://doi.org/10.1038/s41388-018-0331-z

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