A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors.
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.
Chen
Jian-hong
JH
Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Yao
Xiao-hong
XH
Gong
Wanghua
W
Hu
Jinyue
J
Zhou
Xiang-dong
XD
Chen
Keqiang
K
Liu
Hong
H
Ping
Yi-fang
YF
Wang
Ji Ming
JM
Bian
Xiu-wu
XW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D044042:Receptors, Formyl Peptide / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D042461:Vascular Endothelial Growth Factor A; C510003:nordy; D009637:Masoprocol; D002118:Calcium