Artikel
Aurora kinase inhibition and radiation therapy enhance the efficacy oftumour treating fields in recurrent glioblastoma treatment
Aurora Kinase Inhibition und Bestrahlung verstärken den Effekt von Tumor-Therapiefeldern in der Therapie von Glioblastom-Rezidiven
Suche in Medline nach
Autoren
Veröffentlicht: | 26. Juni 2020 |
---|
Gliederung
Text
Objective: Tumor Treating Fields (TTFields) have been shown to be effective in prolonging progression-free and overall survival, thereby increasing the rate of two- and five-year survivors of patients with primary glioblastoma. However, the two-year survival rate is still below 50%, and the TTFields effect in recurrent glioblastoma seems to be weaker than in primary therapy. A promising approach to enhance the efficiency of TTFields is the combination with drugs, which extend metaphase-anaphase transition and telophase.
Methods: In the present study we tested the efficacy of the combined treatment of TTFields (1.6 V/cm RMS, 200 kHz) and the Aurora A kinase inhibitor MLN8237 as well as the Aurora B kinase inhibitor AZD 1152 in the established glioma cell line U87-MG and three primary recurrent glioblastoma cell lines. In addition, we tested the additional effect of radiation of the cells before treatment with TTFields and MLN8237 and AZD 1152, respectively.
Results: We found that the combination of TTFields, MLN8237 and AZD 1152, respectively, (75 nmol/l each) and radiation (4Gy – 8Gy; 0,5Gy/min) led to a significant reduction in the number of cells as compared to each treatment alone (Mann-Whitney-U-test, p<0.01). Furthermore, we showed an increased DNA content in PI stained glioblastoma cells suggesting polyploidy and disturbed cell replication. Both light microscope and confocal laser scanning microscope imaging showed morphological changes such as multinuclear cells, increased cell size as well as cytoskeletal modifications due to the combination treatment with TTFields, MLN8237 or AZD 1152 and radiation compared to each treatment alone.
Conclusion: The results presented here demonstrate that the combination of TTFields and Aurora kinase inhibition can be an effective treatment for recurrent glioblastoma. The cytotoxic effect can be augmented by radiation pretreatment. These results resemble those, which we found in primary glioblastoma cell lines indicating that the combination therapy of TTFields and Aurora kinase inhibition is effective in first-line treatment as well as for recurrent glioblastoma.