LAB. INVESTIGATION-HUMAN/ANIMAL TISSUE A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors Jian-hong Chen Æ Xiao-hong Yao Æ Wanghua Gong Æ Jinyue Hu Æ Xiang-dong Zhou Æ Keqiang Chen Æ Hong Liu Æ Yi-fang Ping Æ Ji Ming Wang Æ Xiu-wu Bian Received: 5 February 2007 / Accepted: 1 March 2007 / Published online: 22 March 2007 Ó Springer Science+Business Media B.V. 2007 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 chemoattrac- tants 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. Keywords Nordy Á Glioma Á Chemotaxis Á Formylpeptide receptor (FPR) Á Epidermal growth factor (EGF) Á Vascular endothelial growth factor (VEGF) Introduction Glioma ranges in degree of malignancy from slowly growing low-grade tumors to rapidly growing high-grade 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. J.-h. Chen Á X.-h. Yao Á H. Liu Á Y.-f. Ping Á X.-w. Bian (&) Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China e-mail: bianxiuwu@263.net J.-h. Chen Á J. Hu Á K. Chen Á J. M. Wang (&) Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Building 560, Room 31-40, Frederick, MD 21702-1201, USA e-mail: wangji@mail.ncifcrf.gov J.-h. Chen Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China W. Gong Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA X.-d. Zhou Department of Pharmacy, Division of Basic Medical Science, Third Military Medical University, Chongqing 400038, China 123 J Neurooncol (2007) 84:223–231 DOI 10.1007/s11060-007-9369-4