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

摘要: Hypoxia-inducible factor 1 (HIF-1) plays essential roles in tumor angiogenesis and growth by regulating the transcription of several key genes response to hypoxic stress factors. HIF-1 is a heterodimeric transcriptional activator consisting inducible alpha constitutive beta subunits. In oxygenated cells, proteins containing prolyl hydroxylase domain (PHD) directly sense intracellular oxygen concentrations. PHDs tag HIF-1alpha subunits for polyubiquitination proteasomal degradation hydroxylation using 2-oxoglutarate (2-OX) dioxygen. Our recent studies showed that 2-OX reduces HIF-1alpha, erythropoietin, vascular endothelial (VEGF) expression hepatoma cell line Hep3B when under conditions vitro. Here, we report similar results were obtained Lewis lung cancer (LLC) cells vitro studies. Furthermore, potent antitumor effects mouse dorsal air sac assay murine xenograft model. assay, reduced numbers newly formed vessels induced LLC cells. model, intraperitoneal injection significantly inhibited tissues. Moreover, 5-fluorouracil combined with this which was accompanied reduction Vegf gene These suggest promising anti-angiogenic therapeutic agent.