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Neurotoxicity Research

, Volume 35, Issue 4, pp 797–808 | Cite as

Selenium Enhances the Apoptotic Efficacy of Docetaxel Through Activation of TRPM2 Channel in DBTRG Glioblastoma Cells

  • Kemal Ertilav
  • Mustafa Nazıroğlu
  • Zeki Serdar Ataizi
  • Nady BraidyEmail author
Original Article

Abstract

The rate of mitosis of cancer cells is significantly higher than normal primary cells with increased metabolic needs, which in turn enhances the generation of reactive oxygen species (ROS) production. Higher ROS production is known to increase cancer cell dependence on ROS scavenging systems to counteract the increased ROS. Therapeutic options which selectively modulate the levels of intracellular ROS in cancers are likely candidates for drug discovery. Docetaxel (DTX) has demonstrated antitumor activity in preclinical and clinical studies. It is thought that DTX induces cell death through excessive ROS production and increased Ca2+ entry. The Ca2+ permeable TRPM2 channel is activated by ROS. Selenium (Se) has been previously used to stimulate apoptosis for the treatment of glioblastoma cells resistant to DTX. However, the potential mechanism(s) of the additive effect of DTX on TRPM2 channels in cancer cells remains unclear. The aim of this study was to evaluate the effect of combination therapy of DTX and Se on activation of TRPM2 in DBTRG glioblastoma cells. DBTRG cells were divided into four treatment groups: control, DTX (10 nM for 10 h), Se (1 μM for 10 h), and DTX+Se. Our study showed that apoptosis (Annexin V and propidium iodide), mitochondrial membrane depolarization (JC1), and ROS production levels were increased in DBTRG cells following treatment with Se and DTX respectively. Cell number and viability, and the levels of apoptosis, JC1, ROS, and [Ca2+]i, induced by DTX, were further increased following addition of Se. We also observed an additive increase in the activation of the NAD-dependent DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP-1) activity, which was accompanied by a decline in its essential substrate NAD+. As well, the Se- and DTX-induced increases in intracellular Ca2+ florescence intensity were decreased following treatment with the TRPM2 antagonist N-(p-amylcinnamoyl) anthranilic acid (ACA). Therefore, combination therapy with Se and DTX may represent an effective strategy for the treatment of glioblastoma cells and may be associated with TRPM2-mediated increases in oxidative stress and [Ca2+]i.

Keywords

Apoptosis Docetaxel Glioblastoma Selenium TRPM2 channel 

Abbreviations

ACA

N-(p-amylcinnamoyl) anthranilic acid

ADPR

ADP-ribose

Ca2+

Calcium ion

cADPR

Cyclic ADPR

CPx

Cumene hydroperoxide

DBTRG-O5MG

Denver Brain Tumor Research Group O5

DHR 123

Dihydrorhodamine 123

DTX

Docetaxel

JC-1

5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzimidazolylcarbocyanine iodide

MeNAM

N-methyl-nicotinamide

NAD+

Nicotinamide adenine dinucleotide.

NADH

Nicotinamide adenine dinucleotide reduced form

NAM

Nicotinamide

PARP1

Poly (ADP-ribose) polymerase 1

PI

Propidium iodide

ROS

Reactive oxygen species

Se

Selenium

TRPA1

Transient receptor potential ankyrin 1

TRPM2

Transient receptor potential melastatin 2

TRPV1

Transient receptor potential vanilloid 1

Notes

Acknowledgements

The authors wish to thank technician Hulusi Gül (BSN Health, Analysis and Innovation Ltd. Inc. Teknokent, Isparta, Turkey) for their help in performing cell number and cell viability analyses.

Financial Support

The study was supported by BSN Health, Analysis and Innovation Ltd. Inc. Teknokent, Isparta, Turkey (Project No: 2018-02).

Authors’ Contributions

KE, MN, and NB formulated the present hypothesis and MN and NB were responsible for writing the report. MN performed the confocal analyses and the LC-MS analysis. ZSA was responsible for analysis of the data. KE, ZSA, and NB made critical revision of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Kemal Ertilav
    • 1
  • Mustafa Nazıroğlu
    • 2
    • 3
  • Zeki Serdar Ataizi
    • 4
  • Nady Braidy
    • 5
    Email author
  1. 1.Department of Neurosurgery, Faculty of MedicineSuleyman Demirel UniversityIspartaTurkey
  2. 2.Neuroscience Research CenterSuleyman Demirel UniversityIspartaTurkey
  3. 3.Drug Discovery and Development Research Group in Neuroscience, BSN Health, Analysis and Innovation, Goller Bolgesi TeknokentiSuleyman Demirel UniversityIspartaTurkey
  4. 4.Department of NeurosurgeryYunus Emre State HospitalEskişehirTurkey
  5. 5.Centre for Healthy Brain Ageing, School of PsychiatryUniversity of New South WalesSydneyAustralia

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