A synthetic dl-nordihydroguaiaretic acid (Nordy), inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model

PLoS One. 2014 Jan 15;9(1):e85759. doi: 10.1371/journal.pone.0085759. eCollection 2014.

Abstract

The zebrafish (Danio rerio) and their transparent embryos represent a promising model system in cancer research. Compared with other vertebrate model systems, we had previously shown that the zebrafish model provides many advantages over mouse or chicken models to study tumor invasion, angiogenesis, and tumorigenesis. In this study, we systematically investigated the biological features of glioma stem cells (GSCs) in a zebrafish model, such as tumor angiogenesis, invasion, and proliferation. We demonstrated that several verified anti-angiogenic agents inhibited angiogenesis that was induced by xenografted-GSCs. We next evaluated the effects of a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), which revealed anti-tumor activity against human GSCs in vitro by establishing parameters through studying its ability to suppress angiogenesis, tumor invasion, and proliferation. Furthermore, our results indicated that Nordy might inhibit GSCs invasion and proliferation through regulation of the arachidonate 5-lipoxygenase (Alox-5) pathway. Moreover, the combination of Nordy and a VEGF inhibitor exhibited an enhanced ability to suppress angiogenesis that was induced by GSCs. By contrast, even following treatment with 50 µM Nordy, there was no discernible effect on zebrafish embryonic development. Together, these results suggested efficacy and safety of using Nordy in vivo, and further demonstrated that this model should be suitable for studying GSCs and anti-GSC drug evaluation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Agents / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Glioma / drug therapy*
  • Glioma / pathology
  • Glycoproteins / metabolism
  • Humans
  • Masoprocol / analogs & derivatives*
  • Masoprocol / pharmacology
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / physiology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Peptides / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Xenograft Model Antitumor Assays
  • Zebrafish

Substances

  • AC133 Antigen
  • Antigens, CD
  • Antineoplastic Agents
  • Glycoproteins
  • Peptides
  • nordy
  • Masoprocol
  • Receptors, Vascular Endothelial Growth Factor

Grant support

This work was supported by grants from the National Basic Research Program of China (973 Program, Grant No. 2010CB529403), The National Natural Science Fundation of China (Grant No. 81101632 and 81272598), and Liaoning Science and Technology Program (No. 201225109). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.