gms | German Medical Science

Objective: The dysregulation of differentiation mechanisms plays an important role in the pathophysiology of glioblastoma (GBM). Retinoic acid pathway shows an aberrant activation pattern and does not lead to the induction of tumor cells differentiation and apoptosis, but rather induces the expression of pro-survival genes and triggers tumor cell proliferation. The attempts to switch the retinoic acid signaling towards antineoplastic "differentiation" have already been successfully undertaken in cancers such as acute myeloid leukemia. In this project, we studied the combination effect of retinoic acid, LSD1/2 inhibitor tranylcypromine and glutamate antagonist riluzole on the viability of GBM cell cultures.

Methods: We assessed the effect of retinoic acid (5 µM, 10 µM), tranylcypromine (250 µM, 500 µM) and riluzole (25 µM, 50 µM) on the cell viability of U87MG und U251 GBM cells using MTT assay. The cells were treated for 72 h. We applied the drugs in double (retinoic acid + tranylcypromine or riluzole) or triple (riluzole + retinoic acid + tranylcypromine) combinations.

Results: The single treatment with riluzole and tranylcypromine appeared to be highly effective in both cell cultures. The treatment with retinoic acid did not produce a significant effect in U87MG cells, while U251 showed 70% reduction in cell viability. In U87MG, the riluzole-retinoic acid combination surpassed the single treatment. Tranylcypromine and retinoic acid combination was only slightly better than tranylcypromine alone. In U251 cells, the combinations of retinoic acid with either tranylcypromine or riluzole were not better than single treatment regimes. Triple combinations had high effect on the viability of both U87MG and U251 cells.

Conclusion: Single treatment with tranylcypromine and riluzole had a significant effect on the viability of both U87MG and U251 cells, while retinoic acid application seems to be ineffective as a single agent. The triple combinations of retinoic acid, tranylcypromine and riluzole potentiate the effect of single drugs already at their lower concentrations. These findings suggest that such a treatment would be effective independent of the genetic background. Nonetheless the mechanism of this combination effect should be further studied on expression level as well as in functional assays.