A combination of repurposed drugs reduces the proliferation and viability of glioblastoma cells
Aleksandra Sachkova
Doctoral thesis
Date of Examination:
2021-10-12
Date of issue:
2021-10-01
Advisor:
Rohde, Veit Prof. Dr.
Referee:
Rohde, Veit Prof. Dr.
Referee:
Kramm, Christof Prof. Dr.
Referee:
Dressel, Ralf Prof. Dr.
Persistent Address: http://hdl.handle.net/21.11130/00-1735-0000-0008-5926-A
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Abstract
English
Background: Glioblastoma multiforme (GBM) is a malignant primary brain tumour with high rates of recurrence. The tumour is characterized by high molecular diversity. A strategy to simultaneously target different oncogenic pathways together as well as epigenetic modifications could potentially help to overcome the tumour heterogeneity and prevent the development of therapy resistance. This study analysed the in vitro effect of the approved drugs valproic acid, tranylcypromine and riluzole, known for their interaction with epigenetic modifying enzymes and members of the glutamate pathway, singly and in combination with standard chemo- or radiotherapy treatment, in cultured GBM cells. Materials and methods: We examined the effect of the valproic acid, tranylcypromine and riluzole and their combinations, as well as combined with standard temozolomide chemotherapy and radiotherapy on the viability of the U87MG cell line using the MTT assay. Proliferation and cell invasion were evaluated using anti-Ki-67 antibody staining and xCELLigence system. Moreover, we tested the effect of the drugs and their combination on the expression of the tissue factor pathway inhibitor 2 (TFPI2). Results: Valproic acid, tranylcypromine and riluzole produced a significant effect on cell survival. The most prominent effect on cell viability was achieved by the combination of 50 µM riluzole and 10 mM valproic acid and 10 mM valproic acid and 500 µM tranylcypromine. Tranylcypromine significantly enhanced the effect of temozolomide when used in combination, as did valproic acid. The cell proliferation significantly reduced under the combination treatment of temozolomide with valproic acid and tranylcypromine. We observed no additional effect of the radiation on the cell viability. The reduction of invasion was observed comparing single tranylcypromine to its combination with valproic acid or riluzole. The U87MG cells showed a significant upregulation of TFPI2 under the single treatment with VPA or TCA as well as for all combinations of VPA, TCA and riluzole. Conclusion: The combination of repurposed drugs could increase the treatment efficiency of GBM by reducing the cellular viability and proliferation potential as well as by the upregulation of the tumour-suppressor gene expression.
Keywords: brain tumour; glioblastoma; valproic acid; tranylcypromine; riluzole; cell death; U87MG cell culture; proliferation; TFPI2; combined treatment
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Human- und Zahnmedizin [2398]