Open AccessAntitumor effects of 2‐oxoglutarate through inhibition of angiogenesis in a murine tumor model
Author(s) -
Matsumoto Ken,
Obara Naoshi,
Ema Masatsugu,
Horie Masaki,
Naka Ayano,
Takahashi Satoru,
Imagawa Shigehiko
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01249.x
Subject(s) - angiogenesis , vascular endothelial growth factor , cancer research , in vivo , lewis lung carcinoma , in vitro , biology , microbiology and biotechnology , chemistry , biochemistry , cancer , metastasis , vegf receptors , genetics
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. ( Cancer Sci 2009; 100: 1639–1647)