HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Glioblastomas are aggressive brain tumors with poor prognoses, often driven by activated signaling pathways like PI3K.
• Loss of PTEN or EGFR activation in glioblastomas leads to PI3K pathway activation, promoting tumor growth and angiogenesis via VEGF and HIF-1alpha.
• Current glioblastoma treatments are often insufficient, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the anti-angiogenic and anti-tumor effects of HIV protease inhibitors nelfinavir and amprenavir in glioblastoma.
• To determine the impact of these inhibitors on key signaling molecules, including Akt, VEGF, and HIF-1alpha.
• To evaluate the potential of nelfinavir and amprenavir in preclinical glioblastoma models.

Main Methods:

• Assessing the effects of nelfinavir and amprenavir on VEGF and HIF-1alpha expression under normoxic and hypoxic conditions.
• Investigating the role of the PI3K/Akt pathway in mediating the effects of nelfinavir on VEGF.
• Evaluating the impact of nelfinavir on angiogenesis using in vivo Matrigel plug assays.

Main Results:

• Nelfinavir significantly decreased VEGF mRNA and protein secretion, an effect linked to Akt pathway inhibition.
• Both nelfinavir and amprenavir reduced the hypoxia-induced expression of VEGF and HIF-1alpha.
• Nelfinavir's inhibition of HIF-1alpha appeared to be mediated by decreased protein translation.
• In vivo studies demonstrated that nelfinavir effectively reduced angiogenesis.

Conclusions:

• HIV protease inhibitors nelfinavir and amprenavir exhibit anti-angiogenic properties relevant to glioblastoma treatment.
• These drugs modulate critical pathways (PI3K/Akt, VEGF, HIF-1alpha) involved in glioblastoma progression.
• Further clinical investigation of nelfinavir and amprenavir is warranted for glioblastoma therapy.