Influence of glycation on the treatment response of glioma cells to tumour treating fields (TTFields, Optune)
Cynthia Götz (Halle), Konstantin Hauschild (Halle), Paola Schildhauer (Halle), Christian Scheller (Halle), Christian Strauss (Halle), Sandra Leisz (Halle), Maximilian Scheer (Halle)
Glioblastoma (GBM) is a highly aggressive and invasive brain tumour. The most malignant cells use aerobic glycolysis for energy production (Warburg effect), leading to the accumulation of highly reactive by-products such as methylglyoxal (MGO). In our own preliminary work, we have shown that MGO induces glycation of cell surface proteins in GBM cells, which was associated with a more aggressive phenotype with increased invasion.
In order to reduce the invasiveness of tumour cells, the use of alternating electric fields (Tumor Treating Fields, TTFields, Novocure) has been established in recent years in addition to the well-known therapeutic pillars of radiotherapy and chemotherapy. TTFields were able to prolong progression-free and overall survival. In this study, we aim to investigate the effect of preclinical application of TTFields (Inovitro™ system) in combination with GBM cells under the influence of MGO.
GBM cell lines U251, LN229 and U87 were used in this study. Cells were treated with 0.1 and 0.3 mM MGO for 4 h and then exposed to the Inovitro™ system for 48 h and 72 h at the same MGO concentration. The Inovitro™ system was operated with low intensity (1-3 V/cm) and medium frequency (200 kHz) alternating electric fields, which have a selective antimitotic effect on cancer cells. To prove the efficacy of both treatments, cell death was subsequently analysed by cell counting using the Chemometec NucleoCount. In addition, the arrangement of alpha and gamma tubulin was visualised by immunofluorescence.
Application of TTFields was able to reduce the increased proliferation of cells under 0.1 mM MGO. However, treatment with 0.3 mM MGO over the entire period was associated with an increased rate of apoptosis. This effect was enhanced by additional treatment with TTFields. The combination of TTFields and MGO led to a reduction in cell diameter compared to the respective monotherapy. Immunofluorescence imaging showed a concentration of alpha- and gamma-tubulin at the cell poles after treatment with TTFields.
This study shows that TTFields can attenuate the protumorigenic effects of glycation in GBM. However, higher concentrations of MGO in this setting are toxic and TTFields enhance this effect. In further studies, we would like to investigate the molecular background of these observations.