Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment.
Growth factor receptors dysfunction has previously been correlated with glioma cell proliferation, ability to evade apoptosis, neo-angiogenesis and resistance to therapy. Antineoplastic molecules targeting growth factor receptors are in clinical handling, however the efficacy of these compounds has often been limited by the signaling redundancy. Here, we analyzed the effect of AG1433 (a PDGFR inhibitor), SU1498 (a VEGFR inhibitor) and BEZ235 (a PI3K/Akt/mTOR signaling pathways inhibitor) on glioblastoma cells in vitro. For this study, we used a low passage glioblastoma cell line (GB9B). Assessment of cell number over 72 h showed that the growth rate was 0.3024 and the doubling time of GB9B was 2.29 days. Similar cytotoxic effects were observed by using AG1433 and SU1498 treatment, while dual PI3K/Akt/mTOR inhibition by BEZ235 was more efficient in killing glioblastoma cells than individual PDGFR or VEGFR targeting. In SU1498 treated cells, caspase 3 activity was detected 3 hours after the treatment, while activation of caspase 8 and 9 was detected 48 hours later. AG1433 treatment induced caspase 3, 8 and 9, 3 hours after the treatment. BEZ235 treatment resulted in early caspase 3 and 8 activation, 3 hours after the treatment and an activation of caspase 9, 8 hours later.
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Alisa Madalina
AM
Popescu
Department of Neurology, University of Medicine and Pharmacy of Craiova and Clinical Hospital of Neuropsychiatry Craiova Craiova, Romania.
Oana
O
Alexandru
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Corina
C
Brindusa
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Stefana Oana
SO
Purcaru
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Daniela Elise
DE
Tache
Department of Neurosurgery, "Bagdasar-Arseni" Emergency Hospital Bucharest, Romania.
Ligia Gabriela
LG
Tataranu
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Citto
C
Taisescu
Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Anica
A
Dricu
D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007093:Imidazoles; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; C531198:dactolisib
Glioblastoma; PDGFR; RTK; VEGFR