title: Metabolic impact of anti-angiogenic agents on U87 glioma cells.
abstract: BACKGROUND
  Glioma cells not only secrete high levels of vascular endothelial growth factor (VEGF) but also express VEGF receptors (VEGFR), supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev) or VEGFR Tyrosine Kinase Inhibitor (TKI), is poorly known.
  
  
  METHODS
  U87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS).
  
  
  RESULTS
  U87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells.
  
  
  CONCLUSIONS
  Although both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS) might be a valuable marker to assess drug cytotoxicity.
authors.affiliation: Laboratoire de Recherches Biochirurgicales, Université Paris Descartes, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Tanja
authors.initials: T
authors.lastname: Mesti
authors.affiliation: Chemistry, Structure and Properties of Biomaterials and Therapeutic Agents, Unité Mixte de Recherche 7244, Centre National de la Recherche Scientifique, Université Paris 13 Sorbonne Paris Cité, Bobigny, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Savarin
authors.affiliation: Chemistry, Structure and Properties of Biomaterials and Therapeutic Agents, Unité Mixte de Recherche 7244, Centre National de la Recherche Scientifique, Université Paris 13 Sorbonne Paris Cité, Bobigny, France.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Triba
authors.affiliation: Unité de Biologie Intégrative des Adaptations à l'Exercice, Unité 902, Institut National de la Santé et de la Recherche Médicale, Université d'Evry, Evry, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Moyec
authors.affiliation: Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Janja
authors.initials: J
authors.lastname: Ocvirk
authors.affiliation: Laboratoire de Recherches Biochirurgicales, Université Paris Descartes, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Banissi
authors.affiliation: Unité de Formation et de Recherche de Santé, Médecine et Biologie Humaine, Université Paris 13, Bobigny, France; Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France.
authors.forename: Antoine F
authors.initials: AF
authors.lastname: Carpentier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016018:Least-Squares Analysis; D019787:Linoleic Acid / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D025341:Principal Component Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D002934:Cinnamates; D008055:Lipids; C483044:SU 1498; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D019787:Linoleic Acid; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2