An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells

Stem Cell Rev Rep. 2011 Jun;7(2):458-70. doi: 10.1007/s12015-010-9175-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Astrocytes / metabolism
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioma / pathology*
  • Glycoproteins / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Leukotriene B4 / pharmacology
  • Lipoxygenase Inhibitors / pharmacology*
  • Masoprocol / analogs & derivatives*
  • Masoprocol / pharmacology
  • Mice
  • Mice, Nude
  • Nanog Homeobox Protein
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology*
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Octamer Transcription Factor-3 / metabolism
  • Peptides / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • SOXB1 Transcription Factors / metabolism
  • Transplantation, Heterologous
  • Tumor Burden / drug effects

Substances

  • AC133 Antigen
  • Antigens, CD
  • Glial Fibrillary Acidic Protein
  • Glycoproteins
  • Homeodomain Proteins
  • Intermediate Filament Proteins
  • Ki-67 Antigen
  • Lipoxygenase Inhibitors
  • NANOG protein, human
  • NES protein, human
  • Nanog Homeobox Protein
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • nordy
  • Leukotriene B4
  • Masoprocol
  • Arachidonate 5-Lipoxygenase
  • MELK protein, human
  • Protein-Serine-Threonine Kinases