Article
Beneficial role of combination therapy on TFPI2 and cell viability in U87MG glioblastoma cell line
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Authors
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Aleksandra Sachkova
- Department of Neurosurgery, Georg-August University Göttingen, , Göttingen, Deutschland
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Swetlana Sperling
- The Translational Neurooncology Research Group, Department of Neurosurgery, , Georg-August University Göttingen, , Göttingen, Deutschland
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Milena Ninkovic
- The Translational Neurooncology Research Group , Department of Neurosurgery , Georg-August University Göttingen , Göttingen, Deutschland
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Veit Rohde
- Department of Neurosurgery, Georg-August University Göttingen, Göttingen, Deutschland
| Published: | June 9, 2017 |
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Outline
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Objective: Standard treatment of patients diagnosed with glioblastoma includes surgical resection and adjuvant radiochemotherapy. Molecular heterogeneity of glioblastoma is one of the reasons for its high resistance to standard treatment. This could be overcome by simultaneous targeting of several signaling pathways and epigenetic mechanisms. Here we examine the effect of approved drugs; tranylcypromine hydrochloride (2-PCPA), riluzole and valproic acid on the survival and proliferation of U87MG glioblastoma cell lines and on gene expression.
Methods: We measured the effect of tranylcypromine, riluzole and valproic acid and their combinations with temozolomide and radiation on the cell viability of U87MG glioblastoma cells using MTT assay. The effect on proliferation was studied by immunostaining with Ki67 antibody. Changes in gene expression were determined by qPCR.
Results: Riluzole (25, 50, 75 µM), tranylcypromine (250, 500, 1000 µM) and valproic acid (5, 10 mM) alone and in combinations with standard treatment caused significant reduction in the viability of U87MG cells. The best additive effect was achieved by the combinations of valproic acid and riluzole (76%) and valproic acid and tranylcypromine (63,5%). The co-treatment with temozolomide and radiation further increased the effect. The application of valproic acid and tranylcypromine caused significant reduction (3.39%; p<0.05) in cell proliferation. Further on, we observed the upregulation in the mRNA expression of tissue factor pathway inhibitor 2 (TFPI2; x2,5-x4,7) under the treatment of various combinations of the study drugs.
Conclusion: Combinations of tranylcypromine, valproic acid and riluzole alone and in combination with standard treatment increased cell death and inhibited proliferation of U87MG glioblastoma cells. Combination of these drugs also upregulated TFPI2 expression. TFPI2 is a known inhibitor of tumor cell invasion and is downregulated by hypermethylation in various tumors including glioblastoma. Since TFPI2 is a potential inhibitor of invasiveness investigation of tumor progression under these treatments in vivo is required. Moreover, tranylcypromine and valproic acid are known to intervene in the epigenetic regulation mechanisms, which could be a new approach in the treatment of brain tumor.
