Antitumor effects of 2‐oxoglutarate through inhibition of angiogenesis in a murine tumor model

Matsumoto, Ken; Obara, Naoshi; Ema, Masatsugu; Horie, Masaki; Naka, Ayano; Takahashi, Satoru; Imagawa, Shigehiko

doi:10.1111/j.1349-7006.2009.01249.x

Cited by 43 publications

(45 citation statements)

References 41 publications

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“…Matsumuto and colleagues have evaluated the effect of 2-OG, an essential co-factor for PHD and FIH-1 hydroxylase activity, on the production of erythropoietin and VEGF in Hep3B cells, and found that 2-OG dose-dependently inhibited HIF-1a, erythropoietin and VEGF protein levels in Hep3B cells in hypoxic conditions, and also dose-dependently inhibited tube formation in in vitro angiogenesis assays, presumably by enhancing PHD/FIH-1 activity [121]. In a more recent study they reported similar results in Lewis lung cancer cells, in both a mouse dorsal air sac assay and a murine tumour xenograft model [122], in which 2-OG was shown to dose-dependently reduce HIF-1a protein and VEGF mRNA. In addition, 2-OG was also shown to reduce tumour size when injected into mice with solid tumours, suggesting that a similar approach-namely upregulating PHD activitymight be of benefit in arthritis.…”

Section: Angiogenesis Inhibition: Prospects For New Targets In Rasupporting

confidence: 61%

Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience

et al. 2011

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The paradigm of a therapy aimed at inhibiting the formation of blood vessels, which would consequentially deprive cells and tissues of oxygen and nutrients, was born from the concept pioneered by the late Judah Folkman that blood vessel formation is central to the progression and maintenance of diseases which involve cellular metabolism and tissue expansion, and cancer in particular. The prototype targeted angiogenesis inhibitor anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was approved in 2004 for colorectal cancer, and has since been approved for other cancers. Rheumatoid arthritis (RA) is a chronic inflammatory disease, during which inflamed tissue invades and destroys cartilage and bone. The tissue expansion, invasion, expression of cytokines and growth factors and areas of hypoxia which are a feature of RA have resulted in the hypothesis that angiogenesis inhibition may also be beneficial in RA, drawing on the success of bevacizumab. This review focuses on our current understanding of the importance of angiogenesis in RA, and on the lessons which may be learnt from the clinical experiences of angiogenesis blockade, particularly in colorectal cancer.

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Section: Angiogenesis Inhibition: Prospects For New Targets In Rasupporting

confidence: 61%

Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience

et al. 2011

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“…In addition, no evidence of a glycolytic signature could be seen molecularly or by nuclear imaging. Indeed, in vivo findings suggest that IDH mutation-driven decrease in a-ketoglutarate concentrations might affect other HIFdependent or -independent pathways as suggested by others [24][25][26][27]. Moreover, other biochemical and cellular pathways are affected by mutations in IDH1 and IDH2, and the alternative products generated by mutated IDH1 or IDH2 might affect entirely different pathways.…”

Section: Discussionmentioning

confidence: 95%

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

et al. 2011

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Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative (18)F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas.

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“…Lee et al (2008) showed that a reduction in PHD2 leads to enhanced tumour growth and enhanced tumourigenesis. In reciprocal experiments, Matsumoto et al (2006, 2009) found that 2-oxogluturate, a substrate of PHD2, reduced both tumour growth and angiogenesis. Examining the effect of Phd2 deletion on endothelial cells directly, Takeda and Fong (2007) found that loss of Phd2 impaired proliferation.…”

Section: The Role Of Phd2 In Tumour Angiogenesismentioning

confidence: 98%

PHD2 in tumour angiogenesis

Chan

Giaccia

2010

Br J Cancer

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Originally identified as the enzymes responsible for catalysing the oxidation of specific, conserved proline residues within hypoxia-inducible factor-1α (HIF-1α), the additional roles for the prolyl hydroxylase domain (PHD) proteins have remained elusive. Of the four identified PHD enzymes, PHD2 is considered to be the key oxygen sensor, as knockdown of PHD2 results in elevated HIF protein. Several recent studies have highlighted the importance of PHD2 in tumourigenesis. However, there is conflicting evidence as to the exact role of PHD2 in tumour angiogenesis. The divergence seems to be because of the contribution of stromal-derived PHD2, and in particular the involvement of endothelial cells, vs tumour-derived PHD2. This review summarises our current understanding of PHD2 and tumour angiogenesis, focusing on the influences of PHD2 on vascular normalisation and neovascularisation.

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Antitumor effects of 2‐oxoglutarate through inhibition of angiogenesis in a murine tumor model

Cited by 43 publications

References 41 publications

Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience

Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

PHD2 in tumour angiogenesis

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