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Abstract and Figures

Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.
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Molecular and Cellular Biochemistry (2019) 462:195–206
https://doi.org/10.1007/s11010-019-03622-8
Cytotoxic andantiproliferative eects ofthymoquinone onrat C6
glioma cells depend onoxidative stress
N.G.Krylova1· M.S.Drobysh2· G.N.Semenkova2· T.A.Kulahava1· S.V.Pinchuk3· O.I.Shadyro2
Received: 18 July 2018 / Accepted: 23 February 2019 / Published online: 6 September 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its abil-
ity to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes.
Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-
dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50μM) promoted cell-cycle arrest
and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduc-
tion of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state
of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100μM)
induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells
through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action
on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells
to standard chemotherapeutic drugs.
Keywords Glioma· Thymoquinone· Apoptosis· Reactive oxygen species· Mitochondrial dysfunction
Introduction
Glioblastoma, the highest grade glioma tumor, is the most
common malignant brain tumor [1]. Despite considerable
research efforts, glioblastoma remains incurable because
of its infiltrating growth, quick-developing chemotherapy
resistance and the inability of the majority of anticancer
drugs to penetrate blood–brain barrier. Nowadays, only two
chemotherapeutic agents, namely carmustine and temozo-
lomide, have been approved by the USFDA for treating
malignant gliomas [2, 3]. However, glioma and glioblastoma
often show resistance to these drugs due to a variety of cel-
lular mechanisms that include increased efflux of drugs from
cancer cells, autophagy, cancer stem cells and miRNAs [4,
5]. Therefore, the development of more efficient therapeutic
approaches for the treatment for glioblastoma is required. To
date, naturally occurring phytochemicals which have been
revealed to induce apoptosis of tumor cells are considered
to be one of the most prospective compounds for anticancer
therapy [5].
Quinone derivatives are widely used in medicine as
antibacterial and antiviral agents, antimicotics and chemo-
therapeutic compounds [6]. Doxorubicin, one of the high-
effective anticancer quinones, is used for treatment for
diverse types of tumors such as lymphomas, sarcomas of
various etiology and breast cancer. Natural quinones such as
menadione and thymoquinone (TQ, 2-isopropyl-5-methyl-
1,4-benzoquinone) are considered promising chemothera-
peutic drugs [7, 8]. Antitumor activity of TQ has been dem-
onstrated against different tumors invivo and invitro. TQ
has been shown to cross the blood–brain barrier and induce
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1101 0-019-03622 -8) contains
supplementary material, which is available to authorized users.
* T. A. Kulahava
tatyana_kulagova@tut.by
1 Department ofBiophysics, Faculty ofPhysics, Belarusian
State University, 4 Nezavisimosti ave., 220030Minsk,
Belarus
2 Department ofRadiation Chemistry andPharmaceutical
Technologies, Faculty ofChemistry, Belarusian State
University, 14 Leningradskaya st., 220030Minsk, Belarus
3 Institute ofBiophysics andCell Engineering ofNational
Academy ofSciences ofBelarus, 27 Academicheskaya st.,
220072Minsk, Belarus
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... It was observed that the development of cytosolic ROS in glioma cells was increased at a concentration of TQ greater than 20 μM. Maximum iROS production has been detected at 50-70 μM TQ in cells [47]. In our study, we showed that TQ increases iROS generation on glioma cells; therefore, it affects cell viability and apoptosis. ...
... Thus, pro-oxidant agents such as TQ can be considered a viable way to selectively induce cancer cell death while protecting normal cells. To date, several intracellular iROS modulating and GSH-reducing agents have demonstrated anti-tumor activity in preclinical and clinical studies [47,51]. From our obtained results of GSH, it is observed that TQ also decreases the GSH levels on C6 glioma cells in comparison to the control. ...
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... Proteins. It is known that intracellular oxidative stress can modulate redox-dependent Akt and mitogen-activated protein kinase (MAPK) signal transduction pathways, which can lead to apoptosis of cancer cells [80]. The p38 mitogen-activated protein kinase is a member of MAPK family proteins and supports a key role in mediating resistance to anticancer treatments, also promoting cell growth, survival signaling, proliferation, migration, and inflammation [81]. ...
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... Regarding gliomas, early assays in U87MG and T98G cell lines showed that increasing amounts of thymoquinone resulted in significant alterations in cell morphology and impaired viability in a dose-dependent and time-dependent manner in both cell lines, although the wild-type TP53 cell line was more sensitive [395]. DNA damage, cell cycle arrest, inhibition of colony formation, ROS generation, apoptosis induction, and migration impairment were also observed by others [396][397][398][399][400][401]. In most cases, without affecting normal cells [402,403]. ...
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