Glioblastoma cell invasion is targetable by combination treatment with migrastatic inhibitors

AIMS
One of the hallmarks of cancer is cell migration and invasion, a striking feature of glioblastoma (GBM). The highly migratory potential of tumour cells enables recurrence of GBM tumours leading to poor survival and patient death. We recently characterised a panel of migrastatic inhibitors and reported on the ability of glioma cells to overcome drug activity by employing a mesenchymal to amoeboid migratory switch. Here we demonstrate that targeting different signalling pathways involved in cell migration induces synergistic drug activity of single inhibitors.

METHOD
The previously described inhibitors CCG-1423 and Rhosin Hydrochloride were used singly or in combination to target cell migration in established glioma cell lines. Characterisation of drug activity was achieved by 2D and 3D migration and invasion assays and cytoskeletal and morphological changes were assessed by immunofluorescence assays.

RESULTS
When used in single applications, the inhibitors did not have a significant effect on cell migration in 2D and 3D. However, combination treatments led to significantly reduced migration in both 2D and 3D with notable effects on the cytoskeleton as evidenced by changes in focal adhesion dynamics and in actin localisation. Cellular features also changed in response to combination treatment as noted by increase in cell size and adhesion to neighbouring cells.

CONCLUSIONS
The observed effects are in keeping with targeting two distinct signalling pathways driving cells to either adopt amoeboid or mesenchymal cell migration/invasion mechanisms. We propose that a ‘cocktail’ of migrastatic inhibitors should be included in future experimental designs for consideration as novel, complementary treatment strategies in GBM.