Artikel
OTX-008, a selective Galectin-1 inhibitor has antiproliferative effect on human glioblastoma cells
OTX-008, ein selektiver Galectin-1-Inhibitor hat einen antiproliferativen Effekt auf humane Glioblastomzellen
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Veröffentlicht: | 8. Mai 2019 |
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Objective: Galectin-1 is a protein that is involved in tumor cell proliferation, migration, and chemoresistance. The calixarene derivate OTX-008 is designed to bind Galectin-1 as an allosteric inhibitor of carbohydrate binding. Recent studies showed that OTX-008 inhibits cell proliferation and angiogenesis of several solid malignancies in vitro and in vivo. The effect of OTX-008 on GBM cell cultures derived from individual human GBM specimens is not known. The aim of our study was to investigate the antiproliferative effect of OTX-008 on the U87MG cell line, the A172 cell line, patient derived GBM cultures and cultured human astrocytes (HCA).
Methods: Four GBM specimens were intraoperatively retrieved out of the 5-ALA positive tumor areas and cultured in DMEM. In these GBM cultures, in the A172 cell line, U87MG cell line, and in HCA (Cell Systems Corporation, Kirkland WA, USA) Galectin-1 mRNA-expression was determined by quantitative real-time polymerase chain reaction. All cell cultures were treated 24h after seeding with OTX008 (Axon Medchem) and dose finding curves were calculated. Cell viability was determined with MTT-Assay after 72h. ED50 and ED95 of OTX-008 were calculated by Probit-Analysis applying a logit model on logarithmic transformed doses for every cell experiment.
Results: OTX-008 had antiproliferative effects in all 4 human GBM cell cultures with a mean ED50 of 35.34 (95% CI: 30.20–41.44) μM, and a mean ED95 of 112.93 (95% CI: 93.86–139.34) [PJ1] μM. Furthermore, antiproliferative effects were found in the A172 cell line with an ED50 of 32.94 (95% CI: 29.08–37.32) μM, and in the U87 cell line with an ED50 of 17.14 (95% CI: 15.38–19.02) μM. In 2 GBM cultures a low Gal-1 expression (LGE) was determined (0.09 and 0.248), and the 2 other GBM cultures had high Gal-1 expression (HGE). Probit-Analysis calculated an ED50 of 18.43 (95% CI: 15.77–21.12) μM in the LGE group compared to an ED50 of 34.16 (95% CI: 30.71–37.99) μM in the HGE group. Probit analysis of OTX-008 administration in cultured human astrocytes showed no dose-response-relationship.
Conclusion: To the best of our knowledge this is the first report that OTX-008 inhibits cell proliferation in human GBM cell cultures derived from intraoperative specimens. In patient-derived cultures the OTX-008 sensitivity was dependent of Galectin-1 expression. In HCA no influence of OTX-008 on cell viability was observed. Therefore, OTX-008 seems to be a promising novel substance in the therapy of human GBM.