Article
Riluzole treatment of brain tumor initiating cells decreases expression of glucose transporter 3
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Authors
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Milena Ninkovic
- Neuroonkologisches Labor, Klinik für Neurochirurgie, Georg-August Universität Göttingen, Göttingen, Germany
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Swetlana Sperling
- Neuroonkologisches Labor, Klinik für Neurochirurgie, Georg-August Universität Göttingen, Göttingen, Germany
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Aung Thiha
- Abteilung Unfallchirurgie, Plastische- und Wiederherstellungschirurgie Klinik für Unfallchirurgie und Orthopädie, Georg-August Universität Göttingen, Göttingen, Germany
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Veit Rohde
- Neuroonkologisches Labor, Klinik für Neurochirurgie, Georg-August Universität Göttingen, Göttingen, Germany
| Published: | June 2, 2015 |
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Outline
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Objective: Stem-like tumor cells are held responsible for tumor initiation in a variety of cancers, hence also in glioblastoma (GBM), the most lethal and prevalent primary malignant brain tumor in adults. Brain tumor initiating cells (BTICs) also display radio- and chemoresistance, which is thought to contribute to tumor recurrence after treatment. Thus, targeting of BTICs offers a potential model for the follow-up of GBM. Here we investigated the effect of riluzole on BTICs. Riluzole is an approved drug for amyotrophic lateral sclerosis and is under investigation in clinical trials as a substance for melanoma therapy. One of the known mechanisms of action is that riluzole inhibits the glutamate release; interferes with neurotransmitter binding at excitatory amino acid receptors such as GABA receptors and inactivates voltage-dependent sodium channels.
Method: In the present work we examine the influence of riluzole on the development of tumors from BTICs in chorio-allantoic membrane assay (CAM). The tumor size (volume) was analyzed with and without riluzole treatment as well as combination of riluzole and radiotherapy. In in vitro assay, the viable cell population was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The tumors were analyzed immunocytochemically using antibodies against GFAP, Vimentin and CD133. mRNA expression of the following genes was analyzed using qRT-PCR: KCNN3, GDNF, SOX2, NANOG, SLC2A3.
Results: After exposure of BTICs from two different GBM (#11 and #64) to various concentrations of riluzole for 48h and 72 h, cell viability was already significantly reduced after 48 h of riluzole application. mRNA level analysis of KCNN3, GDNF, SOX2, NANOG, SLC1A2, SLC2A3 showed that in both lines SLC2A3 was significantly reduced (for #11 p=0.0548 and for #64 p=0.0100). Implantation of the BITCs in CAM assay (day I) and daily treatment with 50 μM of riluzole (treatment starts after day II of implantation) reduced the tumor growth. The combination of riluzole and radiotherapy further reduces tumor growth.
Conclusions: We could show that riluzole inhibits growth of BTICs from two different GBMs. Inhibition properties of riluzole are most probably due to the down-regulation of the glucose transporter type 3 (SLC2A3, GLUT3), which is known to correlate with poor survival in patients with brain tumors. To our knowledge this is the first time that an effect of riluzole on GLUT3 has been described.
