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Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment
Alisa Madalina Popescu1, Oana Alexandru2, Corina Brindusa1
1Department of Functional Science, University of Medicine and Pharmacy of Craiova Romania.
Abstract:
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.
Insights
Targeting growth factor receptors in glioblastoma shows promise. Dual PI3K/Akt/mTOR inhibition with BEZ235 was more effective than PDGFR or VEGFR inhibitors in killing cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Growth factor receptor dysfunction is linked to glioma progression, apoptosis evasion, angiogenesis, and therapy resistance.
- Targeting growth factor receptors with antineoplastic molecules is a clinical strategy, but signaling redundancy limits efficacy.
- Glioblastoma multiforme (GBM) remains a challenging brain tumor with limited treatment options.
Purpose of the Study:
- To investigate the in vitro efficacy of specific inhibitors targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and PI3K/Akt/mTOR pathways in glioblastoma cells.
- To compare the cytotoxic effects of AG1433 (PDGFR inhibitor), SU1498 (VEGFR inhibitor), and BEZ235 (PI3K/Akt/mTOR inhibitor) on glioblastoma cell growth and apoptosis.
- To analyze the kinetics of caspase activation following treatment with these inhibitors.
Main Methods:
- Utilized a low-passage human glioblastoma cell line (GB9B) for in vitro experiments.
- Assessed glioblastoma cell proliferation over 72 hours to determine growth rate and doubling time.
- Quantified cytotoxic effects and measured caspase 3, 8, and 9 activities following treatment with AG1433, SU1498, and BEZ235.
Main Results:
- AG1433 and SU1498 treatments showed similar cytotoxic effects on glioblastoma cells.
- BEZ235, a dual PI3K/Akt/mTOR inhibitor, demonstrated superior efficacy in killing glioblastoma cells compared to individual PDGFR or VEGFR inhibition.
- Differential caspase activation kinetics were observed: AG1433 induced caspases 3, 8, and 9 within 3 hours, while BEZ235 induced caspases 3 and 8 early (3 hours) and caspase 9 later (8 hours). SU1498 induced caspase 3 early (3 hours) and caspases 8 and 9 later (48 hours).
Conclusions:
- Dual inhibition of PI3K/Akt/mTOR pathways is a more effective strategy for glioblastoma cell killing than targeting PDGFR or VEGFR alone.
- The distinct caspase activation profiles suggest different mechanisms of cell death induction by these targeted therapies.
- These findings highlight the potential of BEZ235 as a therapeutic agent for glioblastoma and underscore the importance of considering signaling pathway redundancy in treatment strategies.
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