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

• Published in: PloS one 2014-01, Vol.9 (1), p.e85759-e85759
• Main Authors: Yang, Xiaojun, Cui, Wei, Yu, Shicang, Xu, Chuan, Chen, Guilai, Gu, Ai, Li, Tingting, Cui, Youhong, Zhang, Xia, Bian, Xiuwu
• Format: Article
• Language: English
• Subjects: AC133 Antigen; Acids; Angiogenesis; Animal models; Animals; Anticancer properties; Antigens, CD - metabolism; Antineoplastic Agents - pharmacology; Antitumor agents; Arachidonate 5-lipoxygenase; Biology; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain tumors; Cell Differentiation; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Comparative analysis; Danio rerio; Education; Embryogenesis; Embryonic growth stage; Embryos; Glioma; Glioma - drug therapy; Glioma - pathology; Glioma cells; Gliomas; Glycoproteins - metabolism; Humans; Kinases; Laboratory animals; Lipoxygenase; Masoprocol - analogs & derivatives; Masoprocol - pharmacology; Medicine; Neoplasm Invasiveness; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - physiology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Nordihydroguaiaretic acid; Pathology; Peptides - metabolism; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - metabolism; Stem cell transplantation; Stem cells; Tumorigenesis; Tumors; Vascular endothelial growth factor; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Zebrafish
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0085759

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.