Endothelin B receptor antagonists block proliferation and induce apoptosis in glioma cells.
The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been documented and ET receptor antagonists have been exploited as potential anticancer drugs. Glioblastoma cell lines express both ETA and ETB receptors and previous works have shown that ETB receptors are involved in the proliferation of different cancer cell types. In this study we have investigated the effects of two structurally unrelated ETB receptor antagonists, BQ788 and A192621, on cell survival, proliferation and apoptosis in 1321-N1, U87 and IPDDCA2 glioma cell lines. BQ788 and A192621 reduced glioma cells viability and proliferation assessed by BrdU incorporation and cell cycle analysis by flow cytometry, while in contrast the ETA receptor antagonist BQ123 had no effect on cell survival. TUNEL assay and immunocytochemical experiments showed that BQ788 and A192621 trigger apoptotic processes mainly via activation of the intrinsic mitochondrial pathway involving caspase-9 activation, AIF release and cytochrome c translocation. Furthermore, treatment with ETB antagonists downregulates ERK- and p38MAPK-dependent pathways but does not affect VEGF mRNA levels. Our findings support the hypothesis that ETB antagonists represent a new promising therapeutic strategy for the treatment of high grade gliomas.
Paolillo
Mayra
M
Dipartimento di Farmacologia Sperimentale ed Applicata, Università di Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
Russo
Marika A
MA
Curti
Daniela
D
Lanni
Cristina
C
Schinelli
Sergio
S
D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D065131:Endothelin B Receptor Antagonists; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C120508:A 192621; D051033:Apoptosis Inducing Factor; D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D011759:Pyrrolidines; D042461:Vascular Endothelial Growth Factor A; C086539:BQ 788; D045304:Cytochromes c; D053453:Caspase 9