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Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme

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Abstract

Purpose

The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation.

Methods

We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen).

Results

We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes.

Conclusion

The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Medical University of Silesia, Medyków 18, Katowice, Poland

    Anna M. Bielecka-Wajdman, Tomasz Ludyga & Ewa Obuchowicz

  2. Department of Biology and Genetics, School of Medicine, Medical University of Silesia, Medyków 18, Katowice, Poland

    Marta Lesiak & Aleksander Sieroń

Authors
  1. Anna M. Bielecka-Wajdman
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  2. Marta Lesiak
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  3. Tomasz Ludyga
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  4. Aleksander Sieroń
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  5. Ewa Obuchowicz
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Corresponding author

Correspondence to Anna M. Bielecka-Wajdman.

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Funding

This work was supported by a Grant from the School of Medicine, Medical University of Silesia, Katowice, Poland (KNW-2-016/N/4/K).

Conflict of interest

All authors declare no conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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No human participants were used in this study.

Additional information

This work was supported by a Grant from the School of Medicine, Medical University of Silesia, Katowice, Poland (KNW-2-016/N/4/K).

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Bielecka-Wajdman, A.M., Lesiak, M., Ludyga, T. et al. Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme. Cancer Chemother Pharmacol 79, 1249–1256 (2017). https://doi.org/10.1007/s00280-017-3329-2

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  • DOI: https://doi.org/10.1007/s00280-017-3329-2

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