Antidepressants Joining the Fight Against Resistant Cancers

Bhargav Patel, Mercer University College of Pharmacy

Glioblastoma multiforme (GBM) is considered a treatment-resistant cancer of the brain with an unknown cause and unfavorable prognosis. Treatment options include surgery and chemotherapy using temozolomide. [1] Glioblastoma cancer cells are stated to possess stem cell-like properties and reside in arterioles, which attempt to protect them against therapy by maintaining a hypoxic environment. [2] These cells may be the cause of GBM’s resistance to conventional therapy and high recurrence rate. The standard treatment to eliminate the glioma stem cell (GSC) population has demonstrated failure and may also promote GSCs by changing non-stem cells to stem cells. [3] Antidepressants are prescribed for various conditions, including chronic pain and anxiety disorder, and have been implicated in modulating the cytotoxic effects of cancer drugs and affecting tumor growth. [4]

Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme [5]
Design In vitro; N= 96 cell cultures
Objective To identify the role of antidepressants in the regulation of the heterogenous nature of glioma stem cells in GBM
Study Groups All drugs compared in 4 environments: hypoxia model (1% oxygen), average hypoxia (2.5 % oxygen), hypoxia-reoxygenation model (1% followed by 3% oxygen), and standard laboratory conditions (20% oxygen)
Methods The human GBM line T98G, a normal human astrocytes line, and the human U87 astrocytoma line were used.  In addition to the antidepressant drugs, the cytostatic drug temozolomide was also used. In the hypoxia-reoxygenation model the cultures were maintained in 1% oxygen for 12 hours and then in 3% oxygen for 12 hours.

The drugs (imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, and escitalopram) were compared with each other in environments of varying oxygenation levels to determine their influence on the GSC phenotype. The 20% oxygen environment served as the control. The drugs were added to trypsinized cell cultures at a concentration of 10 uM or 1 mM temozolomide.  

Fluorochrome-conjugated antibodies against CD44, Sox1, Sox2, Nestin, and Ki67 were added to the cell suspension, and samples were incubated at room temperature for 30 minutes in the dark.  Following staining, excess antibody was washed off, the cell suspension was centrifuged and analyzed with FACS Aria flow cytometer. The GSCs were represented by their phenotypic expression of CD44, Ki67, SOX1, SOX2 and Nestin.

Duration 24 hours
Primary Outcome Measure NADPH-dependent oxidoreductase to convert tetrazolium dye (MTT) in showing cell viability; phenotype profile (CD44, Ki67, Nestin, SOX1, and SOX2 expression) of GSC isolated from T98G cultures
Baseline Characteristics N/A
Results Fluoxetine, mirtazapine, escitalopram and agomelatine did not alter cell viability in all oxygen models: p > 0.05

All antidepressant drugs increased the mitochondrial activity of NHA: p < 0.05

Temozolomide reduced viable NHA cells in all oxygen models compared to untreated astrocytes: p < 0.05

Phenotypic profile of GSCs isolated from T98G cultures
Hypoxia Ki67/CD44 expression was greater in controlled group than antidepressants*
Temozolomide increased CD44 expression in controls*
Average hypoxia Imipramine and amitriptyline decreased expression of CD44/Ki67*
All antidepressants decreased SOX1/2 expression*
Temozolomide increased CD44 expression in controls*
Hypoxia-reoxygenation Changes in expression were similar to those observed in hypoxia model*
Nestin expression increased compared to other conditions*
Standard laboratory conditions CD44, SOX1, SOX2 expression was not detected
All antidepressants decreased Ki67 expression compared to controls*
*p< 0.05
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Antidepressants not only support the elimination of glioma cells but also stimulated viability of normal human astrocytes.

The robust experiment design incorporated multiple oxygen environments to be more inclusive than standard laboratory conditions and avoid incomplete data. Imipramine and amitriptyline showed the highest ability to switch GSCs to a non-GSC phenotype, indicating improved efficacy in reducing GBM’s resistance to treatment and a more treatment-susceptible cancer. Although an effective mechanism was demonstrated, designing large studies with human models that are strong enough to have a clinical impact will always be challenging due to the nature and rarity of the disease. Future studies will have to be financed by associations with vested interest in glioblastoma malignancies considering the generic status of most antidepressants will not incentivize any manufacturers.

 

References:

  1. Gallego O. Nonsurgical treatment of recurrent glioblastoma. Curr. Oncol. 2015;22:e273-e281.
  2. Hira VVV, Ploegmakers KJ, Grevers F, et al. CD133+ and nestin+ glioma stem-like cells reside around CD31+ arterioles in niches that express SDF-1α, CXCR4, osteopontin and cathepsin K. J Histochem Cytochem. 2015;63:481-493.
  3. Auffinger B, Tobias AL, Han Y, et al. Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell death and differentiation. 2014;21(7):1119–1131.
  4. Riblet N, Larson R, Watts BV, Holtzheimer P. Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis. Gen Hosp Psychiatry. 2014;36:466–473.
  5. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol. 1995;48:1407–1412.
  6. 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. 2017;79(6):1249-1256.
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