The metabolite 3-hydroxiglutaric acid effectively reduces glioblastoma growth in vivo by affecting the structural integrity of tumor vasculature.
3-Hydroxiglutaric acid (3-OH-GA) is a disease-specific metabolite that accumulates in tissues and body fluids of patients with Glutaric aciduria type I (GAI) and has been associated with vascular abnormalities in these kindreds. Here, we demonstrate that 3-OH-GA also affects the integrity of tumor vessels leading to tumor growth inhibition in a subcutaneous model of human glioblastoma multiforme (GBM). This effect correlated with a marked decrease of VE-Cadherin expression in endothelium of 3-OH-GA-treated tumors. Furthermore, in vitro observations indicated also a direct effect of 3-OH-GA in glioma cells that showed defective mitosis and significant proliferation inhibition. In summary, the GAI-specific metabolite 3-OH-GA significantly inhibited growth of GBM xenografts by affecting the structural integrity of tumor blood vessels and in addition by causing defective mitosis and proliferation inhibition of tumor cells.
Department of Oncology and Hematology with Section Pneumology, Oncology Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ferrer@uke.de
Leticia
L
Oliveira-Ferrer
Jasmin
J
Wellbrock
Melanie
M
Braig
Marianne
M
Klokow
Jessica
J
Hauschild
Carsten
C
Bokemeyer
Walter
W
Fiedler
Suleyman
S
Ergun
Gunter
G
Schuch
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology*; D005977:Glutarates / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis
C108959:3-hydroxyglutaric acid; D018076:DNA, Complementary; D005977:Glutarates