Endothelin B receptor antagonists block proliferation and induce apoptosis in glioma cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Endothelin (ET)-1 promotes cancer cell proliferation and survival.
• ET receptor antagonists are investigated as anticancer agents.
• Glioblastoma cells express both ETA and ETB receptors, with ETB receptors implicated in cancer cell proliferation.

Purpose of the Study:

• To investigate the effects of ETB receptor antagonists BQ788 and A192621 on glioma cell lines.
• To determine the impact of these antagonists on cell survival, proliferation, and apoptosis.
• To elucidate the molecular pathways involved in the ETB antagonist-mediated effects.

Main Methods:

• Utilized glioma cell lines (1321-N1, U87, IPDDCA2).
• Assessed cell viability and proliferation using BrdU incorporation and cell cycle analysis via flow cytometry.
• Investigated apoptosis using TUNEL assay and immunocytochemistry, focusing on caspase-9 activation, AIF release, and cytochrome c translocation.
• Examined the modulation of ERK and p38 MAPK pathways and VEGF mRNA levels.

Main Results:

• BQ788 and A192621 significantly reduced glioma cell viability and proliferation.
• The ETA receptor antagonist BQ123 showed no effect on cell survival.
• ETB antagonists induced apoptosis primarily through the intrinsic mitochondrial pathway, involving caspase-9 activation, AIF release, and cytochrome c translocation.
• Treatment with ETB antagonists downregulated ERK and p38 MAPK pathways but did not affect VEGF mRNA levels.

Conclusions:

• ETB receptor antagonists BQ788 and A192621 demonstrate potent anti-glioma activity.
• These antagonists trigger apoptosis via the intrinsic mitochondrial pathway.
• ETB antagonists represent a promising therapeutic strategy for high-grade gliomas.