Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model
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概要
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Hypoxia-inducible factor 1 (HIF-1) plays essential roles in tumor angiogenesis and growth by regulating the transcription of several key genes in response to hypoxic stress and growth factors. HIF-1 is a heterodimeric transcriptional activator consisting of inducible α and constitutive β subunits. In oxygenated cells, proteins containing the prolyl hydroxylase domain (PHD) directly sense intracellular oxygen concentrations. PHDs tag HIF-1α subunits for polyubiquitination and proteasomal degradation by prolyl hydroxylation using 2-oxoglutarate (2-OX) and dioxygen. Our recent studies showed that 2-OX reduces HIF-1α, erythropoietin, and vascular endothelial growth factor (VEGF) expression in the hepatoma cell line Hep3B when under hypoxic conditions in vitro. Here, we report that similar results were obtained in Lewis lung cancer (LLC) cells in in vitro studies. Furthermore, 2-OX showed potent antitumor effects in a mouse dorsal air sac assay and a murine tumor xenograft model. In the dorsal air sac assay, 2-OX reduced the numbers of newly formed vessels induced by LLC cells. In a murine tumor xenograft model, intraperitoneal injection of 2-OX significantly inhibited tumor growth and angiogenesis in tumor tissues. Moreover, 5-fluorouracil combined with 2-OX significantly inhibited tumor growth in this model, which was accompanied by reduction of Vegf gene expression and inhibited angiogenesis in tumor tissues. These results suggest that 2-OX is a promising anti-angiogenic therapeutic agent.
- Wiley-Blackwellの論文
- 2009-09-10
著者
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TAKAHASHI Satoru
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Me
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Ema Masatsugu
Department Of Biomolecular Sciences Graduate School Of Life Science Tohoku University
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IMAGAWA Shigehiko
Doctoral Program of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of
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OBARA Naoshi
Division of Hematology, Institute of Clinical Medicine
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Obara Naoshi
Division Of Hematology Institute Of Clinical Medicine University Of Tsukuba
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Imagawa Shigehiko
Doctoral Program Of Sports Medicine Graduate School Of Comprehensive Human Sciences University Of Ts
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Matsumoto Ken
Division Of Respiratory Medicine Department Of Medicine Nihon University School Of Medicine
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HORIE Masaki
Doctoral Program of Sports Medicine, University of Tsukuba
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NAKA Ayano
Doctoral Program of Sports Medicine, University of Tsukuba
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Naka Ayano
Doctoral Program Of Sports Medicine University Of Tsukuba
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Imagawa Shigehiko
Doctoral Program Of Sports Medicine University Of Tsukuba
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Horie Masaki
Doctoral Program Of Sports Medicine University Of Tsukuba
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Takahashi Satoru
Dep. Of Anatomy And Embryology Inst. Of Basic Medical Sciences Graduate School Of Comprehensive Huma
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Takahashi Satoru
Department Of Anatomy And Embryology Biomolecular And Integrated Medical Sciences Graduate School Of
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Matsumoto Ken
Dep. Of Anatomy And Embryology Inst. Of Basic Medical Sciences Graduate School Of Comprehensive Huma
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Ema Masatsugu
Dep. Of Anatomy And Embryology Inst. Of Basic Medical Sciences Graduate School Of Comprehensive Huma
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Matsumoto Ken
Division Of Laboratory Medicine Department Of Pathology And Microbiology
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EMA Masatsugu
Department of Anatomy and Embryology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba
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