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

• Published in: Cancer chemotherapy and pharmacology Vol. 79; no. 6; pp. 1249 - 1256
• Main Authors: Bielecka-Wajdman, Anna M., Lesiak, Marta, Ludyga, Tomasz, Sieroń, Aleksander, Obuchowicz, Ewa
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2017; Springer Nature B.V
• Subjects: Adjuvant therapy; Amitriptyline; Antidepressants; Antidepressive Agents - therapeutic use; Antineoplastic Agents, Alkylating - pharmacology; Astrocytes; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain tumors; Cancer Research; CD44 antigen; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy, Adjuvant; Citalopram; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Drugs; Fluoxetine; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - pathology; Glioma; Glioma - drug therapy; Glioma - pathology; Glioma cells; Human performance; Humans; Hypoxia; Hypoxia - pathology; Imipramine; Malignancy; Medicine; Medicine & Public Health; Mitochondria; Mitochondria - drug effects; Neoplastic Stem Cells; Nestin; Oncology; Original Article; Oxygen; Pharmacology/Toxicology; Silence; Stem cells; Supplements; Temozolomide; Therapy; Tricyclic antidepressants; Viability; Xenograft Model Antitumor Assays; Antidepressant drugs in glioma therapy; Glioma stem cells; Glioma malignancy; Adjuvant therapy in glioma
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3329-2

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.