A synthetic dl-nordihydroguaiaretic acid (Nordy), inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model.
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.
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Xiaojun
X
Yang
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Wei
W
Cui
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Shicang
S
Yu
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Chuan
C
Xu
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Guilai
G
Chen
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Ai
A
Gu
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Tingting
T
Li
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Youhong
Y
Cui
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Xia
X
Zhang
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Xiuwu
X
Bian
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D010455:Peptides; C510003:nordy; D009637:Masoprocol; D040262:Receptors, Vascular Endothelial Growth Factor