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A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors

  • Lab. Investigation-Human/Animal Tissue
  • Published:
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Abstract

Nordy is a chiral compound synthesized based on the structure of a natural lipoxygenase (LO) inhibitor nordihydroguaiaretic acid (NDGA) from plants. The aim of the present study is to investigate the effect of Nordy on malignant human glioma cell responses to chemoattractants and growth promoting signals. We found that Nordy, in a non-cytotoxic concentration range, potently inhibited the chemotaxis and calcium flux of a human glioblastoma cell line U87 induced by a formylpeptide receptor (FPR) agonist, formyl-methionyl-leucyl-phenylalanine (fMLF) and epidermal growth factor (EGF). U87 cells treated by Nordy also showed a significantly impaired proliferation and expression of mRNA for vascular endothelial growth factor (VEGF) induced by fMLF. The chemotactic and proliferation responses of Nordy treated U87 cells to EGF were concomitantly diminished. Further experiments revealed that Nordy did not significantly affect FPR gene expression in U87 cells, but attenuated the activation of a plethora of signaling molecules including ERK1/2, p38, JNK, and Akt when the cells were stimulated by fMLF. EGF-induced EGF receptor phosphorylation was also inhibited in Nordy-treated U87 cells. Moreover, Nordy significantly reduced the tumorigenicity of U87 cells in nude mice. Our results suggest that Nordy is capable of inhibiting glioma cell responses to signals that promote cell motility, growth and production of VEGF. Thus, Nordy may constitute a molecular basis for the development of novel anti-cancer drugs.

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Acknowledgements

The authors thank Dr J. J. Oppenheim for reviewing the manuscript; N. Dunlop for technical support; and Fogle C. and Nolan C. for secretarial assistance. This study was supported in part by fundings from UICC International Cancer Research Technology Transfer Award (No. 661/2002), National Natural Science Foundation of China (NSFC, No.30370552), Key Project of Chongqing Science and Technology Committee (CSTC-2005AA5007), and Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. NO1-CO-12400. Chen JH is supported in part by a fellowship from the Office of the International Affairs, NCI, NIH, USA.

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Authors and Affiliations

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

    Jian-hong Chen, Xiao-hong Yao, Hong Liu, Yi-fang Ping & Xiu-wu Bian

  2. Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Building 560, Room 31-40, Frederick, MD, 21702-1201, USA

    Jian-hong Chen, Jinyue Hu, Keqiang Chen & Ji Ming Wang

  3. Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    Jian-hong Chen

  4. Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, 21702, USA

    Wanghua Gong

  5. Department of Pharmacy, Division of Basic Medical Science, Third Military Medical University, Chongqing, 400038, China

    Xiang-dong Zhou

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  1. Jian-hong Chen
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  2. Xiao-hong Yao
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  9. Ji Ming Wang
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Correspondence to Ji Ming Wang or Xiu-wu Bian.

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The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. All animals used in this research project were cared for and used humanely according to the following policies: The US Public Health Service Policy on Humane Care and Use of Animals; the Guide for the Care and Use of Laboratory Animals; and the US Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Train. The publisher or recipient acknowledges right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

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Chen, Jh., Yao, Xh., Gong, W. et al. A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors. J Neurooncol 84, 223–231 (2007). https://doi.org/10.1007/s11060-007-9369-4

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  • DOI: https://doi.org/10.1007/s11060-007-9369-4

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