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An Inhibitor of Arachidonate 5-Lipoxygenase, Nordy, Induces Differentiation and Inhibits Self-Renewal of Glioma Stem-Like Cells

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Abstract

Recent progress in cancer biology indicates that eradication of cancer stem cells (CSCs) is essential for more effective cancer therapy. Unfortunately, cancer stem cells such as glioma stem-like cells (GSLCs) are often resistant to either radio- or chemotherapy. Therefore, screening and development for novel therapeutic modalities against CSCs has been an important emerging field in cancer research. In this study, we report that a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or “Nordy”), inhibited self-renewal and induced differentiation of GSLCs in vitro and in vivo. We found that Nordy inhibited an enzyme known to be involved in leukemia stem cell and leukemia progression, Alox-5, and attenuated the growth of GSLCs in vitro. Nordy reduced the GSLC pool through a decrease in the CD133+ population and abrogated clonogenicity. Nordy appeared to exert its effect via astrocytic differentiation by up-regulation of GFAP and down-regulation of stemness related genes, rather than by inducing apoptosis of GSLCs. The growth inhibition of xenografted glioma by Nordy was more long-lasting compared with that of the akylating agent BCNU, which exhibited significant relapse on drug discontinuation resulting from an enrichment of GSLCs. Meanwhile, transient exposure to Nordy reduced tumorigenecity of GSLCs and induced differentiation of the xenografts. Taken together, we have identified Alox-5 as a novel target in GSLCs and its inhibition with Nordy exhibits therapeutic implications through inducing GSLC differentiation.

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Acknowledgements

We are indebted to Dr. Wei Sun and Dr. Li-ting Wang (Central Laboratory, Third Military Medical University, Chongqing, China) for expertise in immunofluorescence imaging. This work was supported by grants from the National Basic Research Program of China (973 Program, No.2010CB529403) and the national Natural Science Foundation of China (NSFC Nos. 30725035 and 30930103).

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Authors and Affiliations

  1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    Bin Wang, Shi-cang Yu, Jian-yong Jiang, Lin-tao Zhao, Zhe Wang, Hong Tan, You-hong Cui, Cheng Qian, Yi-fang Ping & Xiu-wu Bian

  2. Department of Immunology, Memorial Sloan-Kettering, New York, USA

    Gavin Wallace Porter

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  1. Bin Wang
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Correspondence to Yi-fang Ping or Xiu-wu Bian.

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This work was supported by grants from the National Basic Research Program of China (973 Program, No.2010CB529403) and the national Natural Science Foundation of China (NSFC Nos. 30725035 and 30930103).

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Wang, B., Yu, Sc., Jiang, Jy. et al. An Inhibitor of Arachidonate 5-Lipoxygenase, Nordy, Induces Differentiation and Inhibits Self-Renewal of Glioma Stem-Like Cells. Stem Cell Rev and Rep 7, 458–470 (2011). https://doi.org/10.1007/s12015-010-9175-9

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